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Introduction: Comprehensive molecular tumor profiling is widely used in the management of patients with cancer. Molecular tumor boards devise treatment strategies based on testing results. In this setting, the Transsectoral Molecular Tumor Board exchange platform Deutschland (TEAM-D) aims to drive peer-to-peer exchange to connect experts in the field. Methods: During the first virtual TEAM-D meeting, participants from 16 German universities and 5 nonacademic institutions discussed five cases with PIK3CA hotspot mutations. Furthermore, an illustrative case vignette was presented. Results: Overall, German caregivers show restraint in administering off-label PIK3CA inhibitor and favor clinical trials in this setting. Conclusion: In the setting of precision oncology, TEAM-D enables virtual case discussion across the different sectors of the German healthcare system. Based on the example of PIK3CA hotspot mutations, TEAM-D demonstrated the value of integrating knowledge from different healthcare professionals. [ABSTRACT FROM AUTHOR]

Simple Summary: As the complexity of medical data and the specificity of cancer treatments increase, the role of Molecular Tumor Boards (MTBs) becomes ever more crucial. These boards expertly utilize detailed patient data to tailor personalized cancer therapies, significantly enhancing treatment outcomes. However, the operational framework for MTBs lacks clarity and uniformity, which challenges their effectiveness on a global scale. To address this, in early 2023, a group of leading experts convened to establish a comprehensive framework designed to optimize MTB functionality locally, nationally, and internationally. This framework outlines ten essential elements for the success of MTBs, including advanced data management, rigorous testing protocols, and effective leadership across all levels of healthcare. Importantly, it emphasizes the necessity of integrating MTBs within both academic and community healthcare settings, as well as into national health systems, to ensure sustainable operations and widespread access to the most advanced care. This initiative promises to equip MTBs with the necessary tools to adapt and thrive in diverse health systems, ensuring that every patient receives the best possible care based on cutting-edge medical data. The increasing volume of information for cancer care, and the evolution of molecularly guided therapies, have increased the need for molecular tumor boards (MTBs), which can integrate such data into personalized treatment plans to improve patient outcomes. However, recommendations for improving the sustainability of MTBs are lacking. A diverse committee of MTB experts was assembled (February–March 2023), with extensive experience in sustainability in healthcare ecosystems. The aim was to identify MTB-related hurdles throughout the patient journey and develop a general framework for MTBs to operate on larger scales locally, nationally, and internationally. The committee identified ten key pillars for sustainable and scalable MTBs, including technical solutions for data integration and visualization, interoperability, learning loops, clinical trial access, legal considerations, criteria for patient testing, decision standardization, making MTBs official bodies for treatment decisions, local leaders, and international networks. The need for scalable frameworks at academic and community levels was recognized, along with integrating MTBs into national health systems to enhance sustainability and ensure optimal treatment decisions. Irrespective of the health ecosystem, the sustainability and scalability of MTBs are essential. Our framework provides guidelines to address this and to help MTBs evolve towards integrated, essential components of the oncology healthcare system. [ABSTRACT FROM AUTHOR]

Abstract Background Next-generation sequencing (NGS) has been introduced to many Korean institutions to support molecular diagnostics in cancer since 2017, when it became eligible for reimbursement by the National Health Insurance Service. However, the uptake of molecularly guided treatment (MGT) based on NGS results has been limited because of stringent regulations regarding prescriptions outside of approved indications, a lack of clinical trial opportunities, and limited access to molecular tumor boards (MTB) at most institutions. The KOSMOS-II study was designed to demonstrate the feasibility and effectiveness of MGT, informed by MTBs, using a nationwide precision medicine platform. Methods The KOSMOS-II trial is a large-scale nationwide master observational study. It involves a framework for screening patients with metastatic solid tumors for actionable genetic alterations based on local NGS testing. It recommends MGT through a remote and centralized MTB meeting held biweekly. MGT can include one of the following options: Tier 1, the therapeutic use of investigational drugs targeting genetic alterations such as ALK, EGFR, ERBB2, BRAF, FH, ROS1, and RET, or those with high tumor mutational burden; Tier 2, comprising drugs with approved indications or those permitted for treatment outside of the indications approved by the Health Insurance Review and Assessment Service of Korea; Tier 3, involving clinical trials matching the genetic alterations recommended by the MTB. Given the anticipated proportion of patients receiving MGT in the range of 50% ± 3.25%, this study aims to enroll 1,000 patients. Patients must have progressed to one or more lines of therapy and undergone NGS before enrollment. Discussion This pragmatic master protocol provides a mass-screening platform for rare genetic alterations and high-quality real-world data. Collateral clinical trials, translational studies, and clinico-genomic databases will contribute to generating evidence for drug repositioning and the development of new biomarkers. Trial registration NCT05525858.

Background: Next-generation sequencing (NGS) has been introduced to many Korean institutions to support molecular diagnostics in cancer since 2017, when it became eligible for reimbursement by the National Health Insurance Service. However, the uptake of molecularly guided treatment (MGT) based on NGS results has been limited because of stringent regulations regarding prescriptions outside of approved indications, a lack of clinical trial opportunities, and limited access to molecular tumor boards (MTB) at most institutions. The KOSMOS-II study was designed to demonstrate the feasibility and effectiveness of MGT, informed by MTBs, using a nationwide precision medicine platform. Methods: The KOSMOS-II trial is a large-scale nationwide master observational study. It involves a framework for screening patients with metastatic solid tumors for actionable genetic alterations based on local NGS testing. It recommends MGT through a remote and centralized MTB meeting held biweekly. MGT can include one of the following options: Tier 1, the therapeutic use of investigational drugs targeting genetic alterations such as ALK, EGFR, ERBB2, BRAF, FH, ROS1, and RET, or those with high tumor mutational burden; Tier 2, comprising drugs with approved indications or those permitted for treatment outside of the indications approved by the Health Insurance Review and Assessment Service of Korea; Tier 3, involving clinical trials matching the genetic alterations recommended by the MTB. Given the anticipated proportion of patients receiving MGT in the range of 50% ± 3.25%, this study aims to enroll 1,000 patients. Patients must have progressed to one or more lines of therapy and undergone NGS before enrollment. Discussion: This pragmatic master protocol provides a mass-screening platform for rare genetic alterations and high-quality real-world data. Collateral clinical trials, translational studies, and clinico-genomic databases will contribute to generating evidence for drug repositioning and the development of new biomarkers. Trial registration: NCT05525858. [ABSTRACT FROM AUTHOR]

Simple Summary: Identifying the mutational landscape of tumors using next-generation sequencing (NGS) has become substantially more common over the past decade, especially in patients with advanced tumors. However, there is still limited real-world evidence for the clinical benefits of NGS-guided precision oncology. This retrospective analysis of breast and gynecological cancer patients referred to our center's multidisciplinary Molecular Tumor Board revealed that treatment recommendations were provided to 63.3% of patients, of whom 29.1% received molecular-matched treatment resulting in significantly prolonged progression-free survival. Commonly altered genes included TP53, PIK3CA, BRCA1/2, and ARID1A. Overall, NGS-guided precision oncology using panel diagnostics demonstrated improved clinical outcomes in a subset of patients with breast and gynecological cancers in a real-world setting. Background: Precision oncology treatments are being applied more commonly in breast and gynecological oncology through the implementation of Molecular Tumor Boards (MTBs), but real-world clinical outcome data remain limited. Methods: A retrospective analysis was conducted in patients with breast cancer (BC) and gynecological malignancies referred to our center's MTB from 2018 to 2023. The analysis covered patient characteristics, next-generation sequencing (NGS) results, MTB recommendations, therapy received, and clinical outcomes. Results: Sixty-three patients (77.8%) had metastatic disease, and forty-four patients (54.3%) had previously undergone three or more lines of systemic treatment. Personalized treatment recommendations were provided to 50 patients (63.3%), while 29 (36.7%) had no actionable target. Ultimately, 23 patients (29.1%) underwent molecular-matched treatment (MMT). Commonly altered genes in patients with pan-gyn tumors (BC and gynecological malignancies) included TP53 (n = 42/81, 51.9%), PIK3CA (n = 18/81, 22.2%), BRCA1/2 (n = 10/81, 12.3%), and ARID1A (n = 9/81, 11.1%). Patients treated with MMT showed significantly prolonged progression-free survival (median PFS 5.5 vs. 3.5 months, p = 0.0014). Of all patients who underwent molecular profiling, 13.6% experienced a major clinical benefit (PFSr ≥ 1.3 and PR/SD ≥ 6 months) through precision oncology. Conclusions: NGS-guided precision oncology demonstrated improved clinical outcomes in a subgroup of patients with gynecological and breast cancers. [ABSTRACT FROM AUTHOR]

Introduction: Personalized medicine poses great opportunities and challenges. While the therapeutic landscape markedly expands, descriptions about status, clinical implementation and real-world benefits of precision oncology and molecular tumor boards (MTB) remain sparse, particularly in the field of genitourinary (GU) cancer. Hence, this study characterized urological MTB cases to better understand the potential role of MTB in uro-oncology. Methods: We analyzed patients with complete data sets being reviewed at an MTB from January 2019 to October 2022, focusing on results of molecular analysis and treatment recommendations. Results: We evaluated 102 patients with GU cancer with a mean patient age of 61.7 years. Prostate cancer (PCa) was the most frequent entity with 52.9% (54/102), followed by bladder cancer (18.6%, 19/102) and renal cell carcinoma (14.7%, 15/102). On average, case presentation at MTB took place 54.9 months after initial diagnosis and after 2.7 previous lines of therapy. During the study period, 49.0% (50/102) of patients deceased. Additional MTB-based treatment recommendations were achieved in a majority of 68.6% (70/102) of patients, with a recommendation for targeted therapy in 64.3% (45/70) of these patients. Only 6.7% (3/45) of patients – due to different reasons – received the recommended MTB-based therapy though, with 33% (1/3) of patients reaching disease control. Throughout the MTB study period, GU cancer case presentations and treatment recommendations increased, while the time interval between initial presentation and final therapy recommendation were decreasing over time. Conclusion: Presentation of uro-oncological patients at the MTB is a highly valuable measure for clinical decision-making. Prospectively, earlier presentation of patients at the MTB and changing legislative issues regarding comprehensive molecular testing and targeted treatment approval might further improve patients’ benefits from comprehensive molecular diagnostics. [ABSTRACT FROM AUTHOR]

Background: Clinical samples are irreplaceable, and their transformation into searchable and reusable digital biobanks is critical for conducting statistically empowered retrospective and integrative research studies. Currently, mainly data-independent acquisition strategies are employed to digitize clinical sample cohorts comprehensively. However, the sensitivity of DIA is limited, which is why selected marker candidates are often additionally measured targeted by parallel reaction monitoring. Methods: Here, we applied the recently co-developed hybrid-PRM/DIA technology as a new intelligent data acquisition strategy that allows for the comprehensive digitization of rare clinical samples at the proteotype level. Hybrid-PRM/DIA enables enhanced measurement sensitivity for a specific set of analytes of current clinical interest by the intelligent triggering of multiplexed parallel reaction monitoring (MSxPRM) in combination with the discovery-driven digitization of the clinical biospecimen using DIA. Heavy-labeled reference peptides were utilized as triggers for MSxPRM and monitoring of endogenous peptides. Results: We first evaluated hybrid-PRM/DIA in a clinical context on a pool of 185 selected proteotypic peptides for tumor-associated antigens derived from 64 annotated human protein groups. We demonstrated improved reproducibility and sensitivity for the detection of endogenous peptides, even at lower concentrations near the detection limit. Up to 179 MSxPRM scans were shown not to affect the overall DIA performance. Next, we applied hybrid-PRM/DIA for the integrated digitization of biobanked melanoma samples using a set of 30 AQUA peptides against 28 biomarker candidates with relevance in molecular tumor board evaluations of melanoma patients. Within the DIA-detected approximately 6500 protein groups, the selected marker candidates such as UFO, CDK4, NF1, and PMEL could be monitored consistently and quantitatively using MSxPRM scans, providing additional confidence for supporting future clinical decision-making. Conclusions: Combining PRM and DIA measurements provides a new strategy for the sensitive and reproducible detection of protein markers from patients currently being discussed in molecular tumor boards in combination with the opportunity to discover new biomarker candidates. [ABSTRACT FROM AUTHOR]

Introduction: The objective was to determine the added value of comprehensive molecular profile by whole‐exome and RNA sequencing (WES/RNA‐Seq) in advanced and refractory cancer patients who had no molecular‐based treatment recommendation (MBTR) based on a more limited targeted gene panel (TGP) plus array‐based comparative genomic hybridization (aCGH). Materials and Methods: In this retrospective analysis, we selected 50 patients previously included in the PROFILER trial (NCT01774409) for which no MBT could be recommended based on a targeted 90‐gene panel and aCGH. For each patient, the frozen tumor sample mirroring the FFPE sample used for TGP/aCGH analysis were processed for WES and RNA‐Seq. Data from TGP/aCGH were reanalyzed, and together with WES/RNA‐Seq, findings were simultaneously discussed at a new molecular tumor board (MTB). Results: After exclusion of variants of unknown significance, a total of 167 somatic molecular alterations were identified in 50 patients (median: 3 [1–10]). Out of these 167 relevant molecular alterations, 51 (31%) were common to both TGP/aCGH and WES/RNA‐Seq, 19 (11%) were identified by the TGP/aCGH only and 97 (58%) were identified by WES/RNA‐Seq only, including two fusion transcripts in two patients. A MBTR was provided in 4/50 (8%) patients using the information from TGP/aCGH versus 9/50 (18%) patients using WES/RNA‐Seq findings. Three patients had similar recommendations based on TGP/aCGH and WES/RNA‐Seq. Conclusions: In advanced and refractory cancer patients in whom no MBTR was recommended from TGP/aCGH, WES/RNA‐Seq allowed to identify more alterations which may in turn, in a limited fraction of patients, lead to new MBTR. [ABSTRACT FROM AUTHOR]

IntroductionThe management of cancer patients follows a Diagnostic Therapeutic and Care Pathway (PDTA) approach, aimed at achieving the optimal balance between care and quality of life. To support this process, precision medicine and innovative technologies [e.g., next-generation sequencing (NGS)] allow rapid identification of genetic-molecular alterations useful for the design of PDTA-approved therapies. If the standard approach proves inadequate, the Molecular Tumor Board (MTB), a group comprising specialists from diverse disciplines, can step in to evaluate a broader molecular profile, proposing potential therapies beyond evidence levels I–II or considering enrolment in clinical trials. Our aim is to analyze the role of the MTB in the entire management of patients in our institute and its impact on the strategy of personalized medicine, particularly when all approved treatments have failed.Materials and methodsIn alignment with European and national guidelines, a panel of clinicians and preclinical specialists from our institution was defined as the MTB core team. We designed and approved a procedure for the operation of this multidisciplinary group, which is the only one operating in the Puglia region.Results and discussionIn 29 months (2021–2023), we discussed and analyzed 93 patients. A total of 44% presented pathogenic alterations, of which 40.4% were potentially actionable. Only 11 patients were proposed for enrollment in clinical trials, treatment with off-label drugs, or AIFA (the Italian pharmaceutical agency for drugs)—5% funding. Our process indicators, time to analysis, and number of patient cases discussed are in line with the median data of other European institutions. Such findings underscore both the importance and usefulness of the integration of an MTB process into the care of oncology patients.

Abstract Background High tumor mutational burden (TMB) was reported to predict the efficacy of immune checkpoint inhibitors (ICIs). Pembrolizumab, an anti-PD-1, received FDA-approval for the treatment of unresectable/metastatic tumors with high TMB as determined by the FoundationOne®CDx test. It remains to be determined how TMB can also be calculated using other tests. Results FFPE/frozen tumor samples from various origins were sequenced in the frame of the Institut Curie (IC) Molecular Tumor Board using an in-house next-generation sequencing (NGS) panel. A TMB calculation method was developed at IC (IC algorithm) and compared to the FoundationOne® (FO) algorithm. Using IC algorithm, an optimal 10% variant allele frequency (VAF) cut-off was established for TMB evaluation on FFPE samples, compared to 5% on frozen samples. The median TMB score for MSS/POLE WT tumors was 8.8 mut/Mb versus 45 mut/Mb for MSI/POLE-mutated tumors. When focusing on MSS/POLE WT tumor samples, the highest median TMB scores were observed in lymphoma, lung, endometrial, and cervical cancers. After biological manual curation of these cases, 21% of them could be reclassified as MSI/POLE tumors and considered as “true TMB high.” Higher TMB values were obtained using FO algorithm on FFPE samples compared to IC algorithm (40 mut/Mb [10–3927] versus 8.2 mut/Mb [2.5–897], p

Abstract Background In neuro-oncology, the inclusion of tumor patients in the molecular tumor board has only become increasingly widespread in recent years, but so far there are no standards for indication, procedure, evaluation, therapy recommendations and therapy implementation of neuro-oncological patients. The present work examines the current handling of neuro-oncological patients included in molecular tumor boards in Germany. Methods We created an online based survey with questions covering the handling of neuro-oncologic patient inclusion, annotation of genetic analyses, management of target therapies and the general role of molecular tumor boards in neuro-oncology in Germany. We contacted all members of the Neuro-Oncology working group (NOA) of the German Cancer Society (DKG) by e-mail. Results 38 responses were collected. The majority of those who responded were specialists in neurosurgery or neurology with more than 10 years of professional experience working at a university hospital. Molecular tumor boards (MTB) regularly take place once a week and all treatment disciplines of neuro-oncology patients take part. The inclusions to the MTB are according to distinct tumors and predominantly in case of tumor recurrence. An independently MTB member mostly create the recommendations, which are regularly implemented in the tumor treatment. Recommendations are given for alteration classes 4 and 5. Problems exist mostly within the cost takeover of experimental therapies. The experimental therapies are mostly given in the department of medical oncology. Conclusions Molecular tumor boards for neuro-oncological patients, by now, are not standardized in Germany. Similarities exists for patient inclusion and interpretation of molecular alterations; the time point of inclusion and implementation during the patient treatment differ between the various hospitals. Further studies for standardization and harmonisation are needed. In summary, most of the interviewees envision great opportunities and possibilities for molecular-based neuro-oncological therapy in the future.

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Background: High tumor mutational burden (TMB) was reported to predict the efficacy of immune checkpoint inhibitors (ICIs). Pembrolizumab, an anti-PD-1, received FDA-approval for the treatment of unresectable/metastatic tumors with high TMB as determined by the FoundationOne®CDx test. It remains to be determined how TMB can also be calculated using other tests. Results: FFPE/frozen tumor samples from various origins were sequenced in the frame of the Institut Curie (IC) Molecular Tumor Board using an in-house next-generation sequencing (NGS) panel. A TMB calculation method was developed at IC (IC algorithm) and compared to the FoundationOne® (FO) algorithm. Using IC algorithm, an optimal 10% variant allele frequency (VAF) cut-off was established for TMB evaluation on FFPE samples, compared to 5% on frozen samples. The median TMB score for MSS/POLE WT tumors was 8.8 mut/Mb versus 45 mut/Mb for MSI/POLE-mutated tumors. When focusing on MSS/POLE WT tumor samples, the highest median TMB scores were observed in lymphoma, lung, endometrial, and cervical cancers. After biological manual curation of these cases, 21% of them could be reclassified as MSI/POLE tumors and considered as "true TMB high." Higher TMB values were obtained using FO algorithm on FFPE samples compared to IC algorithm (40 mut/Mb [10–3927] versus 8.2 mut/Mb [2.5–897], p < 0.001). Conclusions: We herein propose a TMB calculation method and a bioinformatics tool that is customizable to different NGS panels and sample types. We were not able to retrieve TMB values from FO algorithm using our own algorithm and NGS panel. [ABSTRACT FROM AUTHOR]

Advances in molecular tumor diagnostics have transformed cancer care. However, it remains unclear whether precision oncology has the same impact and transformative nature across all malignancies. We conducted a retrospective analysis of patients with human papillomavirus (HPV)-related gynecologic malignancies who underwent comprehensive molecular profiling and subsequent discussion at the interdisciplinary Molecular Tumor Board (MTB) of the University Hospital, LMU Munich, between 11/2017 and 06/2022. We identified a total cohort of 31 patients diagnosed with cervical (CC), vaginal or vulvar cancer. Twenty-two patients (fraction: 0.71) harbored at least one mutation. Fifteen patients (0.48) had an actionable mutation and fourteen (0.45) received a recommendation for a targeted treatment within the MTB. One CC patient received a biomarker-guided treatment recommended by the MTB and achieved stable disease on the mTOR inhibitor temsirolimus for eight months. Factors leading to non-adherence to MTB recommendations in other patient cases included informed patient refusal, rapid deterioration, stable disease, or use of alternative targeted but biomarker-agnostic treatments such as antibody–drug conjugates or checkpoint inhibitors. Despite a remarkable rate of actionable mutations in HPV-related gynecologic malignancies at our institution, immediate implementation of biomarker-guided targeted treatment recommendations remained low, and access to targeted treatment options after MTB discussion remained a major challenge. [ABSTRACT FROM AUTHOR]

Background: Personalized medicine offers targeted therapy options for cancer treatment. However, the decision whether to include a patient into next-generation sequencing (NGS) testing is not standardized. This may result in some patients receiving unnecessary testing while others who could benefit from it are not tested. Typically, patients who have exhausted conventional treatment options are of interest for consideration in molecularly targeted therapy. To assist clinicians in decision-making, we developed a decision support tool using routine data from a precision oncology program. Methods: We trained a machine learning model on clinical data to determine whether molecular profiling should be performed for a patient. To validate the model, the model’s predictions were compared with decisions made by a molecular tumor board (MTB) using multiple patient case vignettes with their characteristics. Results: The prediction model included 440 patients with molecular profiling and 13,587 patients without testing. High area under the curve (AUC) scores indicated the importance of engineered features in deciding on molecular profiling. Patient age, physical condition, tumor type, metastases, and previous therapies were the most important features. During the validation MTB experts made the same decision of recommending a patient for molecular profiling only in 10 out of 15 of their previous cases but there was agreement between the experts and the model in 9 out of 15 cases. Conclusion: Based on a historical cohort, our predictive model has the potential to assist clinicians in deciding whether to perform molecular profiling. [ABSTRACT FROM AUTHOR]

Background Molecular-driven oncology allows oncologists to identify treatments that match a cancer's genomic profile. Clinical trials are promoted as an effective modality to deliver a molecularly matched treatment. We explore the role of geographical accessibility in Italy, and its impact on patient access to clinical trials. Material and Methods We retrospectively reviewed molecular data from a single-institutional case series of patients receiving next-generation sequencing testing between March 2019 and July 2020. Actionable alterations were defined as the ones with at least one matched treatment on Clinicaltrials.gov at the time of genomic report signature. We then calculated the hypothetical distance to travel to reach the nearest assigned clinical trial. Results We identified 159 patients eligible for analysis. One hundred and one could be potentially assigned to a clinical trial in Italy, and the median distance that patients needed to travel to reach the closest location with a suitable clinical trial was 76 km (interquartile range = 127.46 km). Geographical distribution of clinical trials in Italy found to be heterogeneous, with Milan and Naples being the areas with a higher concentration. We then found that the probability of having a clinical trial close to a patient's hometown increased over time, according to registered studies between 2015 and 2020. Conclusions The median distance to be travelled to the nearest trial was generally acceptable for patients, and trials availability is increasing. Nevertheless, many areas are still lacking trials, so efforts are required to increase and homogenize the possibilities to be enrolled in clinical trials for Italian patients with cancer. [ABSTRACT FROM AUTHOR]

Background: In neuro-oncology, the inclusion of tumor patients in the molecular tumor board has only become increasingly widespread in recent years, but so far there are no standards for indication, procedure, evaluation, therapy recommendations and therapy implementation of neuro-oncological patients. The present work examines the current handling of neuro-oncological patients included in molecular tumor boards in Germany. Methods: We created an online based survey with questions covering the handling of neuro-oncologic patient inclusion, annotation of genetic analyses, management of target therapies and the general role of molecular tumor boards in neuro-oncology in Germany. We contacted all members of the Neuro-Oncology working group (NOA) of the German Cancer Society (DKG) by e-mail. Results: 38 responses were collected. The majority of those who responded were specialists in neurosurgery or neurology with more than 10 years of professional experience working at a university hospital. Molecular tumor boards (MTB) regularly take place once a week and all treatment disciplines of neuro-oncology patients take part. The inclusions to the MTB are according to distinct tumors and predominantly in case of tumor recurrence. An independently MTB member mostly create the recommendations, which are regularly implemented in the tumor treatment. Recommendations are given for alteration classes 4 and 5. Problems exist mostly within the cost takeover of experimental therapies. The experimental therapies are mostly given in the department of medical oncology. Conclusions: Molecular tumor boards for neuro-oncological patients, by now, are not standardized in Germany. Similarities exists for patient inclusion and interpretation of molecular alterations; the time point of inclusion and implementation during the patient treatment differ between the various hospitals. Further studies for standardization and harmonisation are needed. In summary, most of the interviewees envision great opportunities and possibilities for molecular-based neuro-oncological therapy in the future. [ABSTRACT FROM AUTHOR]

Background: The Taiwan Oncology Society (TOS) and the Taiwan Society of Pathology (TSP) have collaborated to present a joint position paper on the molecular tumor boards (MTBs) within the medical institutions of Taiwan. Materials and Methods: To raise awareness of MTBs among health-care professionals, policymakers, and the public, a total of 20 experts from TOS and TSP formulated a joint consensus statement through a voting process. Results: The joint statement proposes key recommendations: (1) MTB discussions encompass diverse molecular analyses including next-generation sequencing (NGS), RNA sequencing, whole-exon sequencing, and whole-genomic sequencing addressing relevant genomic changes, tumor mutation burden, microsatellite instability, and specific biomarkers for certain cancers. (2) MTB meetings should involve multidisciplinary participants who receive regular updates on NGS-related clinical trials. (3) Prioritize discussing cases with unique clinical needs, gene alterations lacking treatments, untreatable neoplasms, or oncogenes unresponsive to targeted therapies. (4) Base MTB discussions on comprehensive patient data, including genetics, pathology, timing of specimen collection, and NGS outcomes. (5) MTBs offer treatment recommendations: standard therapies, off-label use, clinical trials, genetic counseling, and multidisciplinary reviews. (6) MTB effectiveness can be gauged by member composition, case reviews, treatment suggestions, and patient outcomes. Encourage government incentives for MTB engagement. Conclusion: The primary aim of this initiative is to promote the advancement of precision oncology in Taiwan. [ABSTRACT FROM AUTHOR]

Abstract Introduction The objective was to determine the added value of comprehensive molecular profile by whole‐exome and RNA sequencing (WES/RNA‐Seq) in advanced and refractory cancer patients who had no molecular‐based treatment recommendation (MBTR) based on a more limited targeted gene panel (TGP) plus array‐based comparative genomic hybridization (aCGH). Materials and Methods In this retrospective analysis, we selected 50 patients previously included in the PROFILER trial (NCT01774409) for which no MBT could be recommended based on a targeted 90‐gene panel and aCGH. For each patient, the frozen tumor sample mirroring the FFPE sample used for TGP/aCGH analysis were processed for WES and RNA‐Seq. Data from TGP/aCGH were reanalyzed, and together with WES/RNA‐Seq, findings were simultaneously discussed at a new molecular tumor board (MTB). Results After exclusion of variants of unknown significance, a total of 167 somatic molecular alterations were identified in 50 patients (median: 3 [1–10]). Out of these 167 relevant molecular alterations, 51 (31%) were common to both TGP/aCGH and WES/RNA‐Seq, 19 (11%) were identified by the TGP/aCGH only and 97 (58%) were identified by WES/RNA‐Seq only, including two fusion transcripts in two patients. A MBTR was provided in 4/50 (8%) patients using the information from TGP/aCGH versus 9/50 (18%) patients using WES/RNA‐Seq findings. Three patients had similar recommendations based on TGP/aCGH and WES/RNA‐Seq. Conclusions In advanced and refractory cancer patients in whom no MBTR was recommended from TGP/aCGH, WES/RNA‐Seq allowed to identify more alterations which may in turn, in a limited fraction of patients, lead to new MBTR.

Abstract Background Molecular Tumor Boards (MTB) operating in real-world have generated limited consensus on good practices for accrual, actionable alteration mapping, and outcome metrics. These topics are addressed herein in 124 MTB patients, all real-world accrued at progression, and lacking approved therapy options. Methods Actionable genomic alterations identified by tumor DNA (tDNA) and circulating tumor DNA (ctDNA) profiling were mapped by customized OncoKB criteria to reflect diagnostic/therapeutic indications as approved in Europe. Alterations were considered non-SoC when mapped at either OncoKB level 3, regardless of tDNA/ctDNA origin, or at OncoKB levels 1/2, provided they were undetectable in matched tDNA, and had not been exploited in previous therapy lines. Results Altogether, actionable alterations were detected in 54/124 (43.5%) MTB patients, but only in 39 cases (31%) were these alterations (25 from tDNA, 14 from ctDNA) actionable/unexploited, e.g. they had not resulted in the assignment of pre-MTB treatments. Interestingly, actionable and actionable/unexploited alterations both decreased (37.5% and 22.7% respectively) in a subset of 88 MTB patients profiled by tDNA-only, but increased considerably (77.7% and 66.7%) in 18 distinct patients undergoing combined tDNA/ctDNA testing, approaching the potential treatment opportunities (76.9%) in 147 treatment-naïve patients undergoing routine tDNA profiling for the first time. Non-SoC therapy was MTB-recommended to all 39 patients with actionable/unexploited alterations, but only 22 (56%) accessed the applicable drug, mainly due to clinical deterioration, lengthy drug-gathering procedures, and geographical distance from recruiting clinical trials. Partial response and stable disease were recorded in 8 and 7 of 19 evaluable patients, respectively. The time to progression (TTP) ratio (MTB-recommended treatment vs last pre-MTB treatment) exceeded the conventional Von Hoff 1.3 cut-off in 9/19 cases, high absolute TTP and Von Hoff values coinciding in 3 cases. Retrospectively, 8 patients receiving post-MTB treatment(s) as per physician’s choice were noted to have a much longer overall survival from MTB accrual than 11 patients who had received no further treatment (35.09 vs 6.67 months, p = 0.006). Conclusions MTB-recommended/non-SoC treatments are effective, including those assigned by ctDNA-only alterations. However, real-world MTBs may inadvertently recruit patients electively susceptible to diverse and/or multiple treatments.

The increasing volume of information for cancer care, and the evolution of molecularly guided therapies, have increased the need for molecular tumor boards (MTBs), which can integrate such data into personalized treatment plans to improve patient outcomes. However, recommendations for improving the sustainability of MTBs are lacking. A diverse committee of MTB experts was assembled (February–March 2023), with extensive experience in sustainability in healthcare ecosystems. The aim was to identify MTB-related hurdles throughout the patient journey and develop a general framework for MTBs to operate on larger scales locally, nationally, and internationally. The committee identified ten key pillars for sustainable and scalable MTBs, including technical solutions for data integration and visualization, interoperability, learning loops, clinical trial access, legal considerations, criteria for patient testing, decision standardization, making MTBs official bodies for treatment decisions, local leaders, and international networks. The need for scalable frameworks at academic and community levels was recognized, along with integrating MTBs into national health systems to enhance sustainability and ensure optimal treatment decisions. Irrespective of the health ecosystem, the sustainability and scalability of MTBs are essential. Our framework provides guidelines to address this and to help MTBs evolve towards integrated, essential components of the oncology healthcare system.

Simple Summary: Molecular Tumor Boards (MTBs) utilize comprehensive genomic profiling data to identify and evaluate the therapeutical relevance of cancer-specific genomic vulnerabilities enabling tailored personalized medicine. The present study focused on elucidating factors affecting the clinical translation of MTB recommendations utilizing real-world data in a retrospective analysis. Clinical implementation occurred preferentially when MTB recommendations were of high clinical evidence level. In particular, this was true for recommendations involving PARP, PIK3CA, or IDH1/2 inhibitors. However, we also observed a significant therapeutical benefit of implemented treatments of a low clinical evidence level. This illustrates the limitations of interpreting the therapeutical potential of molecularly informed treatment recommendations solely on their clinical evidence level. The findings of the present study may contribute to the identification of strategies to improve the rate of therapeutical implementation in future studies. Molecular Tumor Boards (MTBs) converge state-of-the-art next-generation sequencing (NGS) methods with the expertise of an interdisciplinary team consisting of clinicians, pathologists, human geneticists, and molecular biologists to provide molecularly informed guidance in clinical decision making to the treating physician. In the present study, we particularly focused on elucidating the factors impacting on the clinical translation of MTB recommendations, utilizing data generated from gene panel mediated comprehensive genomic profiling (CGP) of 554 patients at the MTB of the Comprehensive Cancer Center Erlangen, Germany, during the years 2016 to 2020. A subgroup analysis of cases with available follow-up data (n = 332) revealed 139 cases with a molecularly informed MTB recommendation, which was successfully implemented in the clinic in 44 (31.7%) of these cases. Here, the molecularly matched treatment was applied in 45.4% (n = 20/44) of cases for ≥6 months and in 25% (n = 11/44) of cases for 12 months or longer (median time to treatment failure, TTF: 5 months, min: 1 month, max: 38 months, ongoing at data cut-off). In general, recommendations were preferentially implemented in the clinic when of high (i.e., tier 1) clinical evidence level. In particular, this was the case for MTB recommendations suggesting the application of PARP, PIK3CA, and IDH1/2 inhibitors. The main reason for non-compliance to the MTB recommendation was either the application of non-matched treatment modalities (n = 30)/stable disease (n = 7), or deteriorating patient condition (n = 22)/death of patient (n = 9). In summary, this study provides an insight into the factors affecting the clinical implementation of molecularly informed MTB recommendations, and careful considerations of these factors may guide future processes of clinical decision making. [ABSTRACT FROM AUTHOR]

Monitoring ctDNA by liquid biopsies seems to represent the perfect match for precision oncology and its cornerstone clinical framework: the molecular tumour board (MTB). Detecting and scrutinising the success of targeted therapies or tracking and, for that matter, addressing the therapy with the evolutive nature of a tumour are some of the main advancements one considers to be important for the MTB. One challenge is correlating the estimated allele frequency of each identified genetic alteration determined by analysing the ctDNA sequencing results and matching these with the range of suitable drugs, which may limit the simultaneous treatment of all tumour variations. This limitation arises because a new biopsy would typically be required to evaluate the response to treatment. As a result, evaluating the success of MTB recommendations relies on traditional staging methods, highlighting an existing diagnostic gap. Thus, optimising liquid biopsy technology could enhance the efficacy of MTB treatment recommendations and ensuing tailored therapies. Herein, we discuss the prospect of ctDNA analyses in the molecular tumour board. [ABSTRACT FROM AUTHOR]

Receptor tyrosine kinase erythroblastic oncogene B2 (ERBB2), also known as human epidermal growth factor receptor 2 (HER2), represents an oncogenic driver and has been effectively targeted in breast and gastric cancer. Recently, next-generation sequencing (NGS) discovered ERBB2 as a promising therapeutic target in metastatic colorectal cancer (mCRC), where it is altered in 3–5% of patients, but no therapies are currently approved for this use. Herein, we present the experience of a single center in diagnosing actionable genetic ERBB2 alterations using NGS and utilizing the latest therapeutic options. Between October 2019 and December 2022, a total of 107 patients with advanced CRC underwent molecular analysis, revealing actionable ERBB2 mutations in two patients and ERBB2 amplifications in two other patients. These findings correlated with immunohistochemical (IHC) staining. Of these four patients, two were treated with trastuzumab-deruxtecan (T-DXd). We present two exemplary cases of patients with actionable ERBB2 alterations to demonstrate the effectiveness of T-DXd in heavily pretreated ERBB2-positive mCRC patients and the need for early molecular profiling. To fully exploit the potential of this promising treatment, earlier molecular profiling and the initiation of targeted therapies are essential. [ABSTRACT FROM AUTHOR]

Purpose: Due to poor outcomes and limited treatment options, patients with advanced bone and soft tissue sarcomas (BS/STS) may undergo comprehensive molecular profiling of tumor samples to identify possible therapeutic targets. The aim of this study was to determine the impact of routine molecular profiling in the setting of a dedicated precision oncology program in patients with BS/STS in a German large-volume sarcoma center. Methods: 92 BS/STS patients who received comprehensive genomic profiling (CGP) and were subsequently discussed in our molecular tumor board (MTB) between 2016 and 2022 were included. Patient records were retrospectively reviewed, and the clinical impact of NGS-related findings was analyzed. Results: 89.1% of patients had received at least one treatment line before NGS testing. At least one molecular alteration was found in 71 patients (82.6%). The most common alterations were mutations in TP53 (23.3% of patients), followed by PIK3CA and MDM2 mutations (9.3% each). Druggable alterations were identified, and treatment recommended in 32 patients (37.2%). Of those patients with actionable alterations, ten patients (31.2%) received personalized treatment and six patients did benefit from molecular-based therapy in terms of a progression-free survival ratio (PFSr) > 1.3. Conclusion: Our single-center experience shows an increasing uptake of next-generation sequencing (NGS) and highlights current challenges of implementing precision oncology in the management of patients with BS/STS. A relevant number of patients were diagnosed with clinically actionable alterations. Our results highlight the potential benefit of NGS in patients with rare cancers and currently limited therapeutic options. [ABSTRACT FROM AUTHOR]

Background: Japan's health insurance covers multigene panel testing. This study aimed to determine the potential availability and utility of gene panel testing clinically in gynecologic oncology. Methods: We analyzed the characteristics of patients with gynecologic cancer who underwent gene panel testing using FoundationOne® CDx or OncoGuide™ NCC Oncopanel between November 2019 and October 2022. Results: Out of 102 patients analyzed, 32, 18, 43, 8, and 1 had cervical, endometrial, ovarian cancers, sarcoma, and vaginal cancer, respectively. Druggable gene alteration was found in 70 patients (68.6%; 21 with cervical cancer, 15 with endometrial cancer, 28 with ovarian cancer, 5 with sarcoma, and 1 with other). The most common druggable gene alteration was PIK3CA mutation (n = 21), followed by PTEN mutation (n = 12) and high tumor mutation burden (TMB-H) (n = 11). TMB-H was detected in 5 patients with cervical cancer, 5 with endometrial cancer, and 1 with endometrial stromal sarcoma. Eleven patients (10.8%) received molecularly targeted therapy according to their gene aberrations. Gene panel testing was mostly performed when the second-line treatment was ineffective. Of all 102 patients, 60 did not have recommended treatment, and 15 died or had worsened conditions before obtaining the test results. Conclusion: Through multigene panel testing, although many patients had druggable gene alterations, 10.8% of them received the recommended treatment. TMB-H was mainly observed in cervical/endometrial cancer, suggesting its potential as a therapeutic biomarker of immune checkpoint inhibitors. Furthermore, patients' prognosis and performance status should be considered before performing the test. [ABSTRACT FROM AUTHOR]

Background: In the metastatic setting, cancer patients may not benefit from standard care regimes and their diseases undergo drug resistance due to tumour cell heterogeneity and genomic landscape complexity. In recent years, there have been several attempts to personalise the diagnostic-therapeutic path and to propose novel strategies based on not only histological test results but also on each patient's clinical history and molecular biology. Profiling molecular tests allows physicians to investigate the single tumour genomic landscape and to promote targeted approaches. The Molecular Tumour Board (MTB) is a multidisciplinary committee dedicated to selecting individualised and targeted therapeutic strategies appropriate for patients suffering from diseases that present resistance to standard care. Materials and Methods: Our MTB settled in "Azienda Ospedaliero Universitaria delle Marche", Ancona (AN), Italy, and includes oncologists, molecular biologists, geneticists, and other specialists. Clinical cases are referred by physicians to the MTB, through the Cancer and Research Centre of the Marche Region (CORM), through a telemedicine platform. Four possible molecular profiles are available: FoundationOne® CDx e FoundationOne®Liquid CDx and two local Next Generation Sequencing (NGS) panels, with 16 DNA genes and 10 RNA genes respectively. The resulting genetic mutations and their analyses are evaluated by all the members of the Board and a report for each patient is provided with medical recommendations. Results: from June 2021 to May 2023, we collected data from 97 referral patients (M: 49, F: 48). The mean age was 60.6 years (range 22–83 years). 90 cases were approved for testing. Only seven patients were not eligible for genomic profiling. In two patients who were eligible, molecular profiling was not performed because a tissue sample was not available. Off-label therapy was recommended for three patients. 5% of cases (5/88) showed addressable driver mutations associated with an existing targeted therapy and were immediately enrolled. Conclusions: MTB presents a powerful tool for offering precise medical goals. Our Department of Clinical Oncology also takes advantage of the important role of multidisciplinary teams, through the establishment of CORM and MTB meetings, within which there is the chance to perform NGS-based analyses. It will be important in the future to implement the use of genomic profiling to improve personalised care and to guide the choice of suitable therapies and more appropriate management of patients. [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinoma (ccRCC) treatment has undergone three major paradigm shifts in recent years, first with the introduction of molecular targeted therapies, then with immune checkpoint inhibitors, and, more recently, with immune-based combinations. However, to date, molecular predictors of response to targeted agents have not been identified for ccRCC. The WHO 2022 classification of renal neoplasms introduced the molecularly defined RCC class, which is a first step in the direction of a better molecular profiling of RCC. We reviewed the literature data on known genomic alterations of clinical interest in ccRCC, discussing their prognostic and predictive role. In particular, we explored the role of VHL, mTOR, chromatin modulators, DNA repair genes, cyclin-dependent kinases, and tumor mutation burden. RCC is a tumor whose pivotal genomic alterations have pleiotropic effects, and the interplay of these effects determines the tumor phenotype and its clinical behavior. Therefore, it is difficult to find a single genomic predictive factor, but it is more likely to identify a signature of gene alterations that could impact prognosis and response to specific treatment. To accomplish this task, the interpolation of large amounts of clinical and genomic data is needed. Nevertheless, genomic profiling has the potential to change real-world clinical practice settings. [ABSTRACT FROM AUTHOR]

Introduction: Advanced urothelial carcinoma remains aggressive and very hard to cure, while new treatments will pose a challenge for clinicians and healthcare funding policymakers alike. The U-CHANGE Project aimed to redesign the current model of care for advanced urothelial carcinoma patients to identify limitations ("as is" scenario) and recommend future actions ("to be" scenario). Methods: Twenty-three subject-matter experts, divided into three groups, analyzed the two scenarios as part of a multidimensional consensus process, developing statements for specific domains of the disease, and a simplified Delphi methodology was used to establish consensus among the experts. Results: Recommended actions included increasing awareness of the disease, increased training of healthcare professionals, improvement of screening strategies and care pathways, increased support for patients and caregivers and relevant recommendations from molecular tumor boards when comprehensive genomic profiling has to be provided for appropriate patient selection to ad hoc targeted therapies. Discussion: While the innovative new targeted agents have the potential to significantly alter the clinical approach to this highly aggressive disease, the UCHANGE Project experience shows that the use of these new agents will require a radical shift in the entire model of care, implementing sustainable changes which anticipate the benefits of future treatments, capable of targeting the right patient with the right agent at different stages of the disease. [ABSTRACT FROM AUTHOR]

Background: Precision oncology treatments are being applied more commonly in breast and gynecological oncology through the implementation of Molecular Tumor Boards (MTBs), but real-world clinical outcome data remain limited. Methods: A retrospective analysis was conducted in patients with breast cancer (BC) and gynecological malignancies referred to our center’s MTB from 2018 to 2023. The analysis covered patient characteristics, next-generation sequencing (NGS) results, MTB recommendations, therapy received, and clinical outcomes. Results: Sixty-three patients (77.8%) had metastatic disease, and forty-four patients (54.3%) had previously undergone three or more lines of systemic treatment. Personalized treatment recommendations were provided to 50 patients (63.3%), while 29 (36.7%) had no actionable target. Ultimately, 23 patients (29.1%) underwent molecular-matched treatment (MMT). Commonly altered genes in patients with pan-gyn tumors (BC and gynecological malignancies) included TP53 (n = 42/81, 51.9%), PIK3CA (n = 18/81, 22.2%), BRCA1/2 (n = 10/81, 12.3%), and ARID1A (n = 9/81, 11.1%). Patients treated with MMT showed significantly prolonged progression-free survival (median PFS 5.5 vs. 3.5 months, p = 0.0014). Of all patients who underwent molecular profiling, 13.6% experienced a major clinical benefit (PFSr ≥ 1.3 and PR/SD ≥ 6 months) through precision oncology. Conclusions: NGS-guided precision oncology demonstrated improved clinical outcomes in a subgroup of patients with gynecological and breast cancers.

The application of molecular tumor profiles in clinical decision making remains a challenge. To aid in the interpretation of complex biomarkers, molecular tumor boards (MTBs) have been established worldwide. In the present study, we show that a multidisciplinary approach is essential to the success of MTBs. Our MTB, consisting of pediatric oncologists, pathologists, and pharmacists, evaluated 115 cases diagnosed between March 2016 and September 2021. If targetable mutations were identified, pharmacists aided in the evaluation of treatment options based on drug accessibility. Treatable genetic alterations detected through molecular testing most frequently involved the cell cycle. For 85% of the cases evaluated, our MTB provided treatment recommendations based on the patient’s history and results of molecular tumor testing. Only three patients, however, received MTB-recommended targeted therapy, and only one of these patients demonstrated an improved clinical outcome. For the remaining patients, MTB-recommended treatment often was not administered because molecular tumor profiling was not performed until late in the disease course. For the three patients who did receive MTB-recommended therapy, such treatment was not administered until months after diagnosis due to physician preference. Thus, the education of healthcare providers regarding the benefits of targeted therapy may increase acceptance of these novel agents and subsequently improve patient survival.

BackgroundDespite the putatively targetable genomic landscape of high-grade gliomas, the long-term survival benefit of genomically-tailored targeted therapies remains discouraging.MethodsUsing glioblastoma (GBM) as a representative example of high-grade gliomas, we evaluated the clonal architecture and distribution of hotspot mutations in 388 GBMs from the Cancer Genome Atlas (TCGA). Mutations were matched with 54 targeted therapies, followed by a comprehensive evaluation of drug biochemical properties in reference to the drug’s clinical efficacy in high-grade gliomas. We then assessed clinical outcomes of a cohort of patients with high-grade gliomas with targetable mutations reviewed at the Johns Hopkins Molecular Tumor Board (JH MTB; n = 50).ResultsAmong 1,156 sequence alterations evaluated, 28.6% represented hotspots. While the frequency of hotspot mutations in GBM was comparable to cancer types with actionable hotspot alterations, GBMs harbored a higher fraction of subclonal mutations that affected hotspots (7.0%), compared to breast cancer (4.9%), lung cancer (4.4%), and melanoma (1.4%). In investigating the biochemical features of targeted therapies paired with recurring alterations, we identified a trend toward higher lipid solubility and lower IC50 in GBM cell lines among drugs with clinical efficacy. The drugs’ half-life, molecular weight, surface area and binding to efflux transporters were not associated with clinical efficacy. Among the JH MTB cohort of patients with IDH1 wild-type high-grade gliomas who received targeted therapies, trametinib monotherapy or in combination with dabrafenib conferred radiographic partial response in 75% of patients harboring BRAF or NF1 actionable mutations. Cabozantinib conferred radiographic partial response in two patients harboring a MET and a PDGFRA/KDR amplification. Patients with IDH1 wild-type gliomas that harbored actionable alterations who received genotype-matched targeted therapy had longer progression-free (PFS) and overall survival (OS; 7.37 and 14.72 respectively) than patients whose actionable alterations were not targeted (2.83 and 4.2 months respectively).ConclusionWhile multiple host, tumor and drug-related features may limit the delivery and efficacy of targeted therapies for patients with high-grade gliomas, genotype-matched targeted therapies confer favorable clinical outcomes. Further studies are needed to generate more data on the impact of biochemical features of targeted therapies on their clinical efficacy for high-grade gliomas.

Purpose: For patients with cancer of unknown primary (CUP), treatment options are limited. Precision oncology, the interplay of comprehensive genomic profiling (CGP) and targeted therapies, aims to offer additional treatment options to patients with advanced and hard-to-treat cancers. We aimed to highlight the use of a molecular tumor board (MTB) in the therapeutic management of CUP patients. Methods: In this single-center observational study, CUP patients, presented to the MTB of the Comprehensive Cancer Center Munich LMU, a tertiary care center, were analyzed retrospectively. Descriptive statistics were applied to describe relevant findings. Results: Between June 2016 and February 2022, 61 patients with unfavorable CUP were presented to the MTB, detected clinically relevant variants in 74% (45/61) of patients, of which 64% (29/45) led to therapeutic recommendation. In four out of 29 patients (14%), the treatment recommendations were implemented, unfortunately without resulting in clinical benefit. Reasons for not following the therapeutic recommendation were mainly caused by the physicians' choice of another therapy (9/25, 36%), especially in the context of worsening of general condition, lost to follow-up (7/25, 28%) and death (6/25, 24%). Conclusion: CGP and subsequent presentation to a molecular tumor board led to a high rate of therapeutic recommendations in patients with CUP. Recommendations were only implemented at a low rate; however, late GCP diagnostic and, respectively, MTB referral were found more frequent for the patients with implemented treatment. This contrast underscores the need for early implementation of CGP into the management of CUP patients. [ABSTRACT FROM AUTHOR]

Background and purpose: A subgroup of salivary duct carcinoma (SDC) harbor overexpression of the androgen receptor (AR), and co-occurring mutations in the HRAS- and PIK3CA-genes. The impact of genomic complexity on targeted treatment strategies in advanced cancer is unknown. Materials and methods: We analyzed molecular and clinical data from an institutional molecular tumor board (MTB) to identify AR+, HRAS/PIK3CA comutated SDC. Follow-up was performed within the MTB registrational study or retrospective chart review after approval by the local ethics committee. Response was assessed by the investigator. A systematic literature search was performed in MEDLINE to identify additional clinically annotated cases. Results: 4 patients with AR+ HRAS/PIK3CA co-mutated SDC and clinical followup data were identified from the MTB. An additional 9 patients with clinical follow-up were identified from the literature. In addition to AR overexpression and HRAS and PIK3CA-alterations, PD-L1 expression and Tumor Mutational Burden > 10 Mutations per Megabase were identified as additional potentially targetable alterations. Among evaluable patients, androgen deprivation therapy (ADT) was initiated in 7 patients (1 Partial Response (PR), 2 Stable Disease (SD), 3 Progressive Disease (PD), 2 not evaluable), tipifarnib was initiated in 6 patients (1 PR, 4 SD, 1 PD). One patient each was treated with immune checkpoint inhibition (Mixed Response) and combination therapies of tipifarnib and ADT (SD) and alpelisib and ADT (PR). Conclusion: Available data further support comprehensive molecular profiling of SDC. Combination therapies, PI3K-inhibitors and immune therapy warrant further investigation, ideally in clinical trials. Future research should consider this rare subgroup of SDC. [ABSTRACT FROM AUTHOR]

Purpose: Molecular tumor boards provide precision treatment recommendations based on cancer genomic profile. However, practical barriers limit their benefits. We studied the clinical utility of the precision medicine molecular tumor board (PMMTB) and described challenges with PMMTB implementation. Methods: An observational cohort study included patients reviewed by the PMMTB between September 2015 to December 2017. Patients who had consented to the registry study were included. The primary endpoint of this study was time on treatment (ToT) ratio. Clinical utility was established if the primary endpoint had least 15% of patients achieving a ToT ratio of ≥1.3. Results: Overall, 278 patients were presented to the PMMTB and 113 cases were included in the final analysis. The PMMTB identified at least one nonstandard of care (SOC) clinically actionable mutation for 69.0% (78/113) of cases. In patients who received non-SOC treatment, 43.8% (7/16) achieved a ToT ratio of 1.3 or more (p < 0.001). Fifty-nine patients did not receive non-SOC recommendations. Reasons for not pursuing treatment included 35.6% having response to current treatment, 20.3% died prior to starting or considering PMMTB recommendations, 13.6% pursued other treatment options based on clinician discretion, another 10.2% pursued other treatment options because clinical trials recommended were not geographically accessible, 8.5% had rapid decline of performance status, 6.8% lacked of financial support for treatment, and 5.1% were excluded from clinical trials due to abnormal laboratory values. Conclusion: The regional PMMTB non-SOC recommendations benefitted a majority of patients and additional processes were implemented to assist with non-SOC treatment accessibility. [ABSTRACT FROM AUTHOR]

Simple Summary: Next-generation sequencing (NGS) is a cutting-edge technology that enables rapid, high-throughput sequencing of DNA and RNA. Researchers and clinicians can identify genetic mutations, gene fusions, and other alterations that may drive cancer growth. This is particularly important in precision oncology as it is applied in the context of Molecular Tumor Boards (MTBs). The latter are multidisciplinary teams of experts who use NGS and bioinformatics tools to analyze patients' genetic profiles and develop personalized treatment recommendations for cancer patients. Thus, a crucial process for MTB decision-making is the analysis, compilation, and presentation of high-dimensional sequencing data, which are used for both preparation of and case presentation to all stakeholders. MIRACUM-Pipe precisely addresses these requirements and offers an easy-to-use, one-prompt standardized solution to analyze NGS data, including quality control, variant calling, copy number estimation, annotation, visualization, and report generation. (1) Background: Next-generation sequencing (NGS) of patients with advanced tumors is becoming an established method in Molecular Tumor Boards. However, somatic variant detection, interpretation, and report generation, require in-depth knowledge of both bioinformatics and oncology. (2) Methods: MIRACUM-Pipe combines many individual tools into a seamless workflow for comprehensive analyses and annotation of NGS data including quality control, alignment, variant calling, copy number variation estimation, evaluation of complex biomarkers, and RNA fusion detection. (3) Results: MIRACUM-Pipe offers an easy-to-use, one-prompt standardized solution to analyze NGS data, including quality control, variant calling, copy number estimation, annotation, visualization, and report generation. (4) Conclusions: MIRACUM-Pipe, a versatile pipeline for NGS, can be customized according to bioinformatics and clinical needs and to support clinical decision-making with visual processing and interactive reporting. [ABSTRACT FROM AUTHOR]

Abstract Background A paradigm shift has occurred in cancer chemotherapy from tumor‐specific treatment with cytotoxic agents to personalized medicine with molecular‐targeted drugs. Thus, it is essential to identify genomic alterations and molecular features to recommend effective targeted molecular medicines regardless of the tumor site. Nevertheless, it takes considerable expertise to identify treatment targets from primary‐sequencing data in order to provide drug recommendations. The Molecular Tumor Board (MTB) denotes a platform that integrates clinical and molecular features for clinical decisions. Methods This study retrospectively analyses all the cases of discussion and decision at the MTB in Tohoku University Hospital and summarizes genetic alterations and treatment recommendations. Results The MTB discussed 1003 comprehensive genomic profiling (CGP) tests conducted in patients with solid cancer, and the resulting rate of assessing treatment recommendations was approximately 19%. Among hundreds of genes in the CGP test, only 30 genetic alterations or biomarkers were used to make treatment recommendations. The leading biomarkers that led to treatment recommendations were tumor mutational burden‐high (TMB‐H) (n = 32), ERBB2 amplification (n = 24), BRAF V600E (n = 16), and BRCA1/2 alterations (n = 32). Thyroid cancer accounted for most cancer cases for which treatment recommendation was provided (81.3%), followed by non‐small cell lung cancer (42.4%) and urologic cancer (31.3%). The number of tests performed for gastrointestinal cancers was high (n = 359); however, the treatment recommendations for the same were below average (13%). Conclusion The results of this study may be used to simplify treatment recommendations from the CGP reports and help select patients for testing, thereby increasing the accuracy of personalized medicine.

Advances in molecular tumor diagnostics have transformed cancer care. However, it remains unclear whether precision oncology has the same impact and transformative nature across all malignancies. We conducted a retrospective analysis of patients with human papillomavirus (HPV)-related gynecologic malignancies who underwent comprehensive molecular profiling and subsequent discussion at the interdisciplinary Molecular Tumor Board (MTB) of the University Hospital, LMU Munich, between 11/2017 and 06/2022. We identified a total cohort of 31 patients diagnosed with cervical (CC), vaginal or vulvar cancer. Twenty-two patients (fraction: 0.71) harbored at least one mutation. Fifteen patients (0.48) had an actionable mutation and fourteen (0.45) received a recommendation for a targeted treatment within the MTB. One CC patient received a biomarker-guided treatment recommended by the MTB and achieved stable disease on the mTOR inhibitor temsirolimus for eight months. Factors leading to non-adherence to MTB recommendations in other patient cases included informed patient refusal, rapid deterioration, stable disease, or use of alternative targeted but biomarker-agnostic treatments such as antibody–drug conjugates or checkpoint inhibitors. Despite a remarkable rate of actionable mutations in HPV-related gynecologic malignancies at our institution, immediate implementation of biomarker-guided targeted treatment recommendations remained low, and access to targeted treatment options after MTB discussion remained a major challenge.

IntroductionAdvanced urothelial carcinoma remains aggressive and very hard to cure, while new treatments will pose a challenge for clinicians and healthcare funding policymakers alike. The U-CHANGE Project aimed to redesign the current model of care for advanced urothelial carcinoma patients to identify limitations (“as is” scenario) and recommend future actions (“to be” scenario).MethodsTwenty-three subject-matter experts, divided into three groups, analyzed the two scenarios as part of a multidimensional consensus process, developing statements for specific domains of the disease, and a simplified Delphi methodology was used to establish consensus among the experts.ResultsRecommended actions included increasing awareness of the disease, increased training of healthcare professionals, improvement of screening strategies and care pathways, increased support for patients and caregivers and relevant recommendations from molecular tumor boards when comprehensive genomic profiling has to be provided for appropriate patient selection to ad hoc targeted therapies.DiscussionWhile the innovative new targeted agents have the potential to significantly alter the clinical approach to this highly aggressive disease, the U-CHANGE Project experience shows that the use of these new agents will require a radical shift in the entire model of care, implementing sustainable changes which anticipate the benefits of future treatments, capable of targeting the right patient with the right agent at different stages of the disease.

The application of molecular tumor profiles in clinical decision making remains a challenge. To aid in the interpretation of complex biomarkers, molecular tumor boards (MTBs) have been established worldwide. In the present study, we show that a multidisciplinary approach is essential to the success of MTBs. Our MTB, consisting of pediatric oncologists, pathologists, and pharmacists, evaluated 115 cases diagnosed between March 2016 and September 2021. If targetable mutations were identified, pharmacists aided in the evaluation of treatment options based on drug accessibility. Treatable genetic alterations detected through molecular testing most frequently involved the cell cycle. For 85% of the cases evaluated, our MTB provided treatment recommendations based on the patient's history and results of molecular tumor testing. Only three patients, however, received MTB-recommended targeted therapy, and only one of these patients demonstrated an improved clinical outcome. For the remaining patients, MTB-recommended treatment often was not administered because molecular tumor profiling was not performed until late in the disease course. For the three patients who did receive MTB-recommended therapy, such treatment was not administered until months after diagnosis due to physician preference. Thus, the education of healthcare providers regarding the benefits of targeted therapy may increase acceptance of these novel agents and subsequently improve patient survival. [ABSTRACT FROM AUTHOR]

NGS is increasingly used in precision medicine, but an automated sequencing pipeline that can detect different types of variants (single nucleotide - SNV, copy number - CNV, structural - SV) and does not rely on normal samples as germline comparison is needed. To address this, we developed Onkopipe, a Snakemake-based pipeline that integrates quality control, read alignments, BAM pre-processing, and variant calling tools to detect SNV, CNV, and SV in a unified VCF format without matched normal samples. Onkopipe is containerized and provides features such as reproducibility, parallelization, and easy customization, enabling the analysis of genomic data in precision medicine. Our validation and evaluation demonstrate high accuracy and concordance, making Onkopipe a valuable open-source resource for molecular tumor boards. Onkopipe is being shared as an open source project and is available at https://gitlab.gwdg.de/MedBioinf/mtb/onkopipe. [ABSTRACT FROM AUTHOR]

Background: Metastatic breast cancer (mBC) causes nearly all BC-related deaths. Next-generation sequencing (NGS) technologies allow for the application of personalized medicine using targeted therapies that could improve patients' outcomes. However, NGS is not routinely used in the clinical practice and its cost induces access-inequity among patients. We hypothesized that promoting active patient participation in the management of their disease offering access to NGS testing and to the subsequent medical interpretation and recommendations provided by a multidisciplinary molecular advisory board (MAB) could contribute to progressively overcome this challenge. We designed HOPE (SOLTI-1903) breast cancer trial, a study where patients voluntarily lead their inclusion through a digital tool (DT). The main objectives of HOPE study are to empower mBC patients, gather real-world data on the use of molecular information in the management of mBC and to generate evidence to assess the clinical utility for healthcare systems. Trial design: After self-registration through the DT, the study team validates eligibility criteria and assists patients with mBC in the subsequent steps. Patients get access to the information sheet and sign the informed consent form through an advanced digital signature. Afterwards, they provide the most recent (preferably) metastatic archival tumor sample for DNA-sequencing and a blood sample obtained at the time of disease progression for ctDNA analysis. Paired results are reviewed by the MAB, considering patient's medical history. The MAB provides a further interpretation of molecular results and potential treatment recommendations, including ongoing clinical trials and further (germline) genetic testing. Participants self-document their treatment and disease evolution for the next 2 years. Patients are encouraged to involve their physicians in the study. HOPE also includes a patient empowerment program with educational workshops and videos about mBC and precision medicine in oncology. The primary endpoint of the study was to describe the feasibility of a patient-centric precision oncology program in mBC patients when a comprehensive genomic profile is available to decide on a subsequent line of treatment. [ABSTRACT FROM AUTHOR]

Purpose: In 2016, the University of Munich Molecular Tumor Board (MTB) was implemented to initiate a precision oncology program. This review of cases was conducted to assess clinical implications and functionality of the program, to identify current limitations and to inform future directions of these efforts. Methods: Charts, molecular profiles, and tumor board decisions of the first 1000 consecutive cases (01/2016–03/2020) were reviewed. Descriptive statistics were applied to describe relevant findings. Results: Of the first 1000 patients presented to the MTB; 914 patients received comprehensive genomic profiling. Median age of patients was 56 years and 58% were female. The most prevalent diagnoses were breast (16%) and colorectal cancer (10%). Different types of targeted or genome-wide sequencing assays were used; most of them offered by the local department of pathology. Testing was technically successful in 88%. In 41% of cases, a genomic alteration triggered a therapeutic recommendation. The fraction of patients receiving a tumor board recommendation differed significantly between malignancies ranging from over 50% in breast or biliary tract to less than 30% in pancreatic cancers. Based on a retrospective chart review, 17% of patients with an MTB recommendation received appropriate treatment. Conclusion: Based on these retrospective analyses, patients with certain malignancies (breast and biliary tract cancer) tend to be more likely to have actionable variants. The low rate of therapeutic implementation (17% of patients receiving a tumor board recommendation) underscores the importance of meticulous follow-up for these patients and ensuring broad access to innovative therapies for patients receiving molecular tumor profiling. [ABSTRACT FROM AUTHOR]

High-multiplex tissue imaging (HMTI) approaches comprise several novel immunohistological methods that enable in-depth, spatial single-cell analysis. Over recent years, studies in tumor biology, infectious diseases, and autoimmune conditions have demonstrated the information gain accessible when mapping complex tissues with HMTI. Tumor biology has been a focus of innovative multiparametric approaches, as the tumor microenvironment (TME) contains great informative value for accurate diagnosis and targeted therapeutic approaches: unraveling the cellular composition and structural organization of the TME using sophisticated computational tools for spatial analysis has produced histopathologic biomarkers for outcomes in breast cancer, predictors of positive immunotherapy response in melanoma, and histological subgroups of colorectal carcinoma. Integration of HMTI technologies into existing clinical workflows such as molecular tumor boards will contribute to improve patient outcomes through personalized treatments tailored to the specific heterogeneous pathological fingerprint of cancer, autoimmunity, or infection. Here, we review the advantages and limitations of existing HMTI technologies and outline how spatial single-cell data can improve our understanding of pathological disease mechanisms and determinants of treatment success. We provide an overview of the analytic processing and interpretation and discuss how HMTI can improve future routine clinical diagnostic and therapeutic processes. [ABSTRACT FROM AUTHOR]

Abstract Since U.S. President Barack Obama announced the Precision Medicine Initiative in his New Year’s State of the Union address in 2015, the establishment of a precision medicine system has been emphasized worldwide, particularly in the field of oncology. With the advent of next-generation sequencers specifically, genome analysis technology has made remarkable progress, and there are active efforts to apply genome information to diagnosis and treatment. Generally, in the process of feeding back the results of next-generation sequencing analysis to patients, a molecular tumor board (MTB), consisting of experts in clinical oncology, genetic medicine, etc., is established to discuss the results. On the other hand, an MTB currently involves a large amount of work, with humans searching through vast databases and literature, selecting the best drug candidates, and manually confirming the status of available clinical trials. In addition, as personalized medicine advances, the burden on MTB members is expected to increase in the future. Under these circumstances, introducing cutting-edge artificial intelligence (AI) technology and information and communication technology to MTBs while reducing the burden on MTB members and building a platform that enables more accurate and personalized medical care would be of great benefit to patients. In this review, we introduced the latest status of elemental technologies that have potential for AI utilization in MTB, and discussed issues that may arise in the future as we progress with AI implementation.

Abstract Background Structured and harmonized implementation of molecular tumor boards (MTB) for the clinical interpretation of molecular data presents a current challenge for precision oncology. Heterogeneity in the interpretation of molecular data was shown for patients even with a limited number of molecular alterations. Integration of high-dimensional molecular data, including RNA- (RNA-Seq) and whole-exome sequencing (WES), is expected to further complicate clinical application. To analyze challenges for MTB harmonization based on complex molecular datasets, we retrospectively compared clinical interpretation of WES and RNA-Seq data by two independent molecular tumor boards. Methods High-dimensional molecular cancer profiling including WES and RNA-Seq was performed for patients with advanced solid tumors, no available standard therapy, ECOG performance status of 0–1, and available fresh-frozen tissue within the DKTK-MASTER Program from 2016 to 2018. Identical molecular profiling data of 40 patients were independently discussed by two molecular tumor boards (MTB) after prior annotation by specialized physicians, following independent, but similar workflows. Identified biomarkers and resulting treatment options were compared between the MTBs and patients were followed up clinically. Results A median of 309 molecular aberrations from WES and RNA-Seq (n = 38) and 82 molecular aberrations from WES only (n = 3) were considered for clinical interpretation for 40 patients (one patient sequenced twice). A median of 3 and 2 targeted treatment options were identified per patient, respectively. Most treatment options were identified for receptor tyrosine kinase, PARP, and mTOR inhibitors, as well as immunotherapy. The mean overlap coefficient between both MTB was 66%. Highest agreement rates were observed with the interpretation of single nucleotide variants, clinical evidence levels 1 and 2, and monotherapy whereas the interpretation of gene expression changes, preclinical evidence levels 3 and 4, and combination therapy yielded lower agreement rates. Patients receiving treatment following concordant MTB recommendations had significantly longer overall survival than patients receiving treatment following discrepant recommendations or physician’s choice. Conclusions Reproducible clinical interpretation of high-dimensional molecular data is feasible and agreement rates are encouraging, when compared to previous reports. The interpretation of molecular aberrations beyond single nucleotide variants and preclinically validated biomarkers as well as combination therapies were identified as additional difficulties for ongoing harmonization efforts.

Treatment for advanced colorectal cancer is often limited by complex molecular profiles, which promote resistance to systemic agents and targeted monotherapies. Recent studies suggest that a personalized, combinatorial approach of matching drugs to tumor alterations may be more effective. We implemented a precision medicine strategy by forming a Molecular Tumor Board (MTB), a multidisciplinary team of clinicians, scientists, bioinformaticians and geneticists. The MTB integrated molecular profiling information and patient characteristics to develop N‐of‐One treatments for 51 patients with advanced colorectal cancer. All patients had metastatic disease and 63% had received ≥ 3 prior therapy lines. Overall, 34/51 patients (67%) were matched to ≥ 1 drug recommended by the MTB based on individual tumor characteristics, whereas 17/51 (33%) patients received unmatched therapies. Patients who received matched therapy demonstrated significantly longer progression‐free survival (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.21–0.81; P = 0.01) and a trend towards higher clinical benefit rates (41% vs. 18%, P = 0.058) (all multivariate) compared to patients receiving unmatched therapy. The MTB facilitated personalized matching of drugs to tumor characteristics, which was associated with improved progression‐free survival in patients with advanced colorectal cancer.

Simple Summary: Molecular tumor boards (MTBs) aim to translate the results of genomic tests into clinical practice in order to set-up the most appropriate therapeutic strategy for the individual patient. Genomic tests represent a challenge for the Italian National Health System, which must set-up new paths for access to medicines and, at the same time, guarantee economic sustainability. Furthermore, the scientific and clinical skills of clinicians must be guaranteed to follow the complex and rapid evolution of cancer genetics and the availability of agnostic anticancer drugs. This review aims to analyze the role of MTBs in the management of patients with metastatic breast cancer (MBC). Molecular tumor boards (MTBs) are multidisciplinary groups that combine molecular and clinical data from cancer patients in order to formulate treatment recommendations for precision medicine. To date, there is insufficient data to support the use of singleplex or next-generation sequencing (NGS) technologies to select first-line therapy for patients with metastatic breast cancer (MBC), but considering the high number of level II alterations, according to the ESMO scale for clinical actionability of molecular targets (ESCAT), it is suggested to include patients in molecular screening programs in order to be able to offer targeted therapies for specific genomic alterations. This article aims at reviewing the most recent literature related to the most used methodologies/approaches for molecular diagnostics and variants' classification, summarizing the internationally published molecular screening studies in support of MTB activity and, in the end, discussing MTBs' current position and role in Italy, the number of which is increasing, also thanks to the thrust of institutions. [ABSTRACT FROM AUTHOR]