Tumor mutational burden assessment and standardized bioinformatics approach using custom NGS panels in clinical routine.

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.

Integration of proteomics in the molecular tumor board.

Cancer remains one of the most complex and challenging diseases in mankind. To address the need for a personalized treatment approach for particularly complex tumor cases, molecular tumor boards (MTBs) have been initiated. MTBs are interdisciplinary teams that perform in-depth molecular diagnostics to cooperatively and interdisciplinarily advise on the best therapeutic strategy. Current molecular diagnostics are routinely performed on the transcriptomic and genomic levels, aiming to identify tumor-driving mutations. However, these approaches can only partially capture the actual phenotype and the molecular key players of tumor growth and progression. Thus, direct investigation of the expressed proteins and activated signaling pathways provide valuable complementary information on the tumor-driving molecular characteristics of the tissue. Technological advancements in mass spectrometry-based proteomics enable the robust, rapid, and sensitive detection of thousands of proteins in minimal sample amounts, paving the way for clinical proteomics and the probing of oncogenic signaling activity. Therefore, proteomics is currently being integrated into molecular diagnostics within MTBs and holds promising potential in aiding tumor classification and identifying personalized treatment strategies. This review introduces MTBs and describes current clinical proteomics, its potential in precision oncology, and highlights the benefits of multi-omic data integration.

Evaluation of the Geographical Accessibility of Genome-Matched Clinical Trials on a National Experience.

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.

The value of virtual molecular tumor boards for informed clinical decision-making.

Genomic profiling and other new technologies have increased the volume and complexity of information available for guiding clinical decision-making in precision oncology. Consequently, there is a need for multidisciplinary expert teams, in the form of molecular tumor boards (MTBs), who can translate this information into a therapeutic plan, including matching patients to suitable clinical trials. Virtual MTBs (vMTBs) can help to overcome many of the challenges associated with in-person MTBs, such as limited time availability, access to appropriate experts or datasets, or interactions between institutions. However, real-world experience from vMTBs is lacking. Here, we describe oncologists' vMTB experiences and the value of working with multicenter and/or multinational vMTBs. We also address knowledge gaps and barriers that could affect the implementation of vMTBs in routine clinical practice. Case studies from Argentina, Turkey, and Portugal illustrate the value of informed clinical decision-making by vMTBs, including expansion of therapeutic options for patients, faster time to treatment, and the resulting improvement in patient outcomes or impact of vMTB discussions on patients. With the uptake of comprehensive genomic profiling and the evolution of some cancers now being conceptualized as a collection of rare diseases with small patient populations based on molecular profiling, the importance of MTBs has increased in modern cancer management. However, an adjustment in clinical decision-making by healthcare professionals is required and evidence of the added value of vMTBs is lacking. Existing vMTBs and recommendations from participating oncologists could point toward a structured evaluation and analysis of this new platform.

Improved nationwide survival of sarcoma patients with a network of reference centers.

BACKGROUND: We investigated the impact of the implementation of a network of reference centers for sarcomas (NETSARC) on the care and survival of sarcoma patients in France since 2010. PATIENTS AND METHODS: NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor boards (MDTBs), funded by the French National Cancer Institute (INCa) since 2010. Its aims are to improve the quality of diagnosis and care of sarcoma patients. Patients' characteristics, treatments, and outcomes are collected in a nationwide database. The objective of this analysis was to compare the survival of patients in three periods: 2010-2012 (non-exhaustive), 2013-2015, and 2016-2020. RESULTS: A total of 43 975 patients with sarcomas, gastrointestinal stromal tumors (GISTs), or connective tissue tumors of intermediate malignancy were included in the NETSARC+ database since 2010 (n = 9266 before 2013, n = 12 274 between 2013 and 2015, n = 22 435 in 2016-2020). Median age was 56 years, 50.5% were women, and 13.2% had metastasis at diagnosis. Overall survival was significantly superior in the period 2016-2020 versus 2013-2015 versus 2010-2012 for the entire population, for patients >18 years of age, and for both metastatic and non-metastatic patients in univariate and multivariate analyses (P < 0.0001). Over the three periods, we observed a significantly improved compliance to clinical practice guidelines (CPGs) nationwide: the proportion of patients biopsied before surgery increased from 62.9% to 72.6%; the percentage of patients presented to NETSARC MDTBs before first surgery increased from 31.7% to 44.4% (P < 0.0001). The proportion of patients with R0 resection on first surgery increased (from 36.1% to 46.6%), while R2 resection rate decreased (from 10.9% to 7.9%), with a better compliance and improvement in NETSARC centers. CONCLUSIONS: The implementation of the national reference network for sarcoma was associated with an improvement of overall survival and compliance to guidelines nationwide in sarcoma patients. Referral to expert networks for sarcoma patients should be encouraged, though a better compliance to CPGs can still be achieved.

Simultaneous targeted and discovery-driven clinical proteotyping using hybrid-PRM/DIA.

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.

Pragmatic nationwide master observational trial based on genomic alterations in advanced solid tumors: KOrean Precision Medicine Networking Group Study of MOlecular profiling guided therapy based on genomic alterations in advanced Solid tumors (KOSMOS)-II study protocol KCSG AL-22-09.

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.

The role of molecular tumor boards in neuro-oncology: a nationwide survey.

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.

Development of an International Virtual Multidisciplinary Tumor Board for Breast Cancer in Mongolia.

INTRODUCTION: Breast cancer is the most diagnosed cancer among Mongolian women and mortality rates are high. We describe a virtual multi-institutional and multidisciplinary tumor board (MTB) for breast cancer created to assist the National Cancer Center of Mongolia. MATERIALS AND METHODS: A virtual MTB for breast cancer was conducted with participation of two United States and 1 Mongolian cancer centers. A standardized template for presentations was developed. Recommendations were summarized and shared with participants. Collected data included patient demographics, tumor characteristics, stage, imaging and treatments performed, and recommendations. Questions were categorized as treatment, diagnosis, or palliative questions. RESULTS: Fifteen patients were evaluated. Median age was 39 y. 86.7% of breast cancers were invasive ductal cancers and 13.3% were metaplastic carcinomas. 53.3% were estrogen and progesterone receptor positive (ER+/PR+), 60% were HER2+, 13.3% were triple negative, and 26.7% were recurrent. 40% of patients were evaluated with mammography. 6% received positron emission tomography scans for metastatic evaluation. 66.7% of surgical patients received neoadjuvant chemotherapy. Herceptin was administered to 55.6% of patients with Her2+ cancers. Modified radical mastectomy was most commonly performed and reconstruction was rare. Sentinel lymph node biopsy was not performed. 66.7% of ER+/PR+ patients received endocrine therapy. 6.7% of patients received radiation. 75% of MTB questions pertained to treatment. Recommendations were related to systemic therapy (40%), surgical management (33.3%), pathology (13.3%), and imaging (13.3%). CONCLUSIONS: This study illustrates the development of an international, virtual, multi-institutional breast cancer MTB and provides insight into challenges and potential interventions to improve breast cancer care in Mongolia.

A regional virtual case discussion forum in pediatric oncology: Experience of the Pediatric Oncology East and Mediterranean Group.

BACKGROUND: The Pediatric Oncology East and Mediterranean (POEM) group that aims to share expertise among pediatric oncology providers across the Middle East, North Africa, and East Asia region initiated a virtual Case Discussion Forum (CDF) in 2013. METHODS: Meeting records from September 2013 till June 2021 were reviewed. Detailed minutes were available starting August 2016; case data were analyzed including diagnoses, purpose of presentation and recommendations. A 38-item survey assessing perception of benefits, challenges, and opportunities of the forum was distributed to members of the POEM group and results analyzed. RESULTS: A total of 140 cases were presented from 14 countries. After August 2016, 67 cases were presented, and those were analyzed regarding reasons for discussion, barriers, and recommendations. Details are presented in this report, and the most common challenges identified were related to histopathologic/molecular diagnosis (24%), imaging interpretation (18%), resource limitations (12%), and surgical difficulties (9%). A survey was distributed to all POEM members in 28 countries, and 76 responded. The main benefit reported was the provision of recommendations regarding treatment and evaluation, while the main challenges reported were time zone difference and workload. Recognized opportunities included conducting regionally relevant research studies based on clinical problems identified during discussions, and setting guidelines for resource-adapted treatment regimens. CONCLUSIONS: The POEM CDF identified areas for multi-institutional regional studies and led to a twinning project between two centers in the region for improving diagnostic infrastructure. Such forums can identify specific resource limitations in pediatric cancer and direct efforts for targeted capacity building.

Primary Results of Patients with Genitourinary Malignancies Presented at a Molecular Tumor Board.

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.

Multidisciplinary neurofibromatosis conference in the management of patients with neurofibromatosis type 1 and schwannomatosis in a single tertiary care institution.

OBJECTIVE: To evaluate the role of weekly neurofibromatosis (NF) multi-disciplinary conferences (MDC) on the diagnostic and therapeutic plan for patients with NF type 1 (NF1) and schwannomatosis (SWN). MATERIALS AND METHODS: This retrospective study reviewed patients with confirmed or suspected NF1 and SWN discussed in weekly MDC from March to July 2021. Demographic data collected included patient age, sex, pre-conference and post-conference diagnosis, radiological studies reviewed, and provider specialties in attendance. Outcomes reported included changes in imaging interpretation and treatment plans, changes in post-conference diagnosis relative to pre-conference diagnosis, and time to completion of the recommended change in treatment. RESULTS: Data from 17 MDC "pre-conference" lists included 75 patients (38 female, 37 males, mean age (years): 38 (range: 6-80)) with NF1 (52%, 39/75) and SWN (36%, 27/75) discussed over a total of 91 case reviews. 18.7% (14/75) of all patients had NF2-related SWN, and 17.3% (13/75) of all patients had non-NF2 SWN. The MDC led to changes in imaging interpretation in 18.7% and changes in patient management in 74.7% (diagnostic testing (n = 52), surgical plan (n = 24), medical treatment (n = 9), clinical trial status (n = 4), and radiation treatment (n = 1)) of cases. Among patients for whom a change in management was recorded, 91% (62/68) completed at least one recommendation (mean time to completion (days): 41.4 (range: 0-278)). CONCLUSION: Weekly MDC changes the diagnostic and therapeutic management of the majority of patients discussed (74.7%) and promotes a high adherence rate to recommendations (91%).

Evolution of publicly available large language models for complex decision-making in breast cancer care.

PURPOSE: This study investigated the concordance of five different publicly available Large Language Models (LLM) with the recommendations of a multidisciplinary tumor board regarding treatment recommendations for complex breast cancer patient profiles. METHODS: Five LLM, including three versions of ChatGPT (version 4 and 3.5, with data access until September 3021 and January 2022), Llama2, and Bard were prompted to produce treatment recommendations for 20 complex breast cancer patient profiles. LLM recommendations were compared to the recommendations of a multidisciplinary tumor board (gold standard), including surgical, endocrine and systemic treatment, radiotherapy, and genetic testing therapy options. RESULTS: GPT4 demonstrated the highest concordance (70.6%) for invasive breast cancer patient profiles, followed by GPT3.5 September 2021 (58.8%), GPT3.5 January 2022 (41.2%), Llama2 (35.3%) and Bard (23.5%). Including precancerous lesions of ductal carcinoma in situ, the identical ranking was reached with lower overall concordance for each LLM (GPT4 60.0%, GPT3.5 September 2021 50.0%, GPT3.5 January 2022 35.0%, Llama2 30.0%, Bard 20.0%). GPT4 achieved full concordance (100%) for radiotherapy. Lowest alignment was reached in recommending genetic testing, demonstrating a varying concordance (55.0% for GPT3.5 January 2022, Llama2 and Bard up to 85.0% for GPT4). CONCLUSION: This early feasibility study is the first to compare different LLM in breast cancer care with regard to changes in accuracy over time, i.e., with access to more data or through technological upgrades. Methodological advancement, i.e., the optimization of prompting techniques, and technological development, i.e., enabling data input control and secure data processing, are necessary in the preparation of large-scale and multicenter studies to provide evidence on their safe and reliable clinical application. At present, safe and evidenced use of LLM in clinical breast cancer care is not yet feasible.

Upper Aerodigestive Tract Endoscopy Combining Rigid Laryngoscopy and Flexible Endoscopy.

Upper Aerodigestive Tract Endoscopy (UATE) is recommended for initial examination of head and neck squamous cell carcinomas. Reducing delay of initial examination must be a challenge to manage head and neck cancers. We hereby describe the technic combining UATE and flexible endoscopy in a unique general anesthesia with overview of hypopharyngeal, larygeal, tracheal, esophageal, nasopharyngeal sub sites in a unique procedure with system of magnificense and to perform percutaneous gastrostomy during the same time before initiation of therapy.

Genetics and beyond: Precision Medicine Real-World Data for Patients with Cervical, Vaginal or Vulvar Cancer in a Tertiary Cancer Center.

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.

Knowledge bases and software support for variant interpretation in precision oncology.

Precision oncology is a rapidly evolving interdisciplinary medical specialty. Comprehensive cancer panels are becoming increasingly available at pathology departments worldwide, creating the urgent need for scalable cancer variant annotation and molecularly informed treatment recommendations. A wealth of mainly academia-driven knowledge bases calls for software tools supporting the multi-step diagnostic process. We derive a comprehensive list of knowledge bases relevant for variant interpretation by a review of existing literature followed by a survey among medical experts from university hospitals in Germany. In addition, we review cancer variant interpretation tools, which integrate multiple knowledge bases. We categorize the knowledge bases along the diagnostic process in precision oncology and analyze programmatic access options as well as the integration of knowledge bases into software tools. The most commonly used knowledge bases provide good programmatic access options and have been integrated into a range of software tools. For the wider set of knowledge bases, access options vary across different parts of the diagnostic process. Programmatic access is limited for information regarding clinical classifications of variants and for therapy recommendations. The main issue for databases used for biological classification of pathogenic variants and pathway context information is the lack of standardized interfaces. There is no single cancer variant interpretation tool that integrates all identified knowledge bases. Specialized tools are available and need to be further developed for different steps in the diagnostic process.

The Molecular Tumor Board of the Regina Elena National Cancer Institute: from accrual to treatment in real-world.

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.

Management and outcomes of adolescent and young adult sarcoma patients: results from the French nationwide database NETSARC.

BACKGROUND: The initial management of patients with sarcoma is a critical issue. We used the nationwide French National Cancer Institute-funded prospective sarcoma database NETSARC to report the management and oncologic outcomes in adolescents and young adults (AYAs) patients with sarcoma at the national level. PATIENTS AND METHODS: NETSARC database gathers regularly monitored and updated data from patients with sarcoma. NETSARC was queried for patients (15-30 years) with sarcoma diagnosed from 2010 to 2017 for whom tumor resection had been performed. We reported management, locoregional recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) in AYA treated in French reference sarcoma centers (RSC) and outside RSC (non-RSC) and conducted multivariable survival analyses adjusted for classical prognostic factors. RESULTS: Among 3,227 patients aged 15-30 years with sarcoma diagnosed between 2010 and 2017, the study included 2,227 patients with surgery data available, among whom 1,290 AYAs had been operated in RSC, and 937 AYAs in non-RSC. Significant differences in compliance to guidelines were observed including pre-treatment biopsy (RSC: 85.9%; non-RSC 48.1%), pre-treatment imaging (RSC: 86.8%; non-RSC: 56.5%) and R0 margins (RSC 57.6%; non-RSC: 20.2%) (p < 0.001). 3y-OS rates were 81.1% (95%CI 78.3-83.6) in AYA in RSC and 82.7% (95%CI 79.4-85.5) in AYA in non-RSC, respectively. Whereas no significant differences in OS was observed in AYAs treated in RSC and in non-RSC, LRFS and PFS were improved in AYAs treated in RSC compared to AYAs treated in non-RSC (Hazard Ratios (HR): 0.58 and 0.83, respectively). CONCLUSIONS: This study highlights the importance for AYA patients with sarcoma to be managed in national sarcoma reference centers involving multidisciplinary medical teams with paediatric and adult oncologists.

Off to boarding school: Exploring how physicians learn in Tumor Board.

BACKGROUND: Tumor Board (TB) is a multidisciplinary care conference tradition in adult and pediatric oncology. The Commission on Cancer requires cancer programs to hold multidisciplinary cancer case conferences. Data support improvements in clinical decision-making due to TB and perception of learning value. Data are lacking on how physician participants learn in this environment. METHODS: Our exploratory, qualitative research study rooted in naturalistic inquiry explored how physician participants learn in TB. Fifteen participants were purposefully sampled and completed semi-structured interviews. Interviews were recorded, transcribed, and analyzed to produce themes. RESULTS: Five themes arose: (i) mutual educational goals by participating stakeholders are beneficial to educational experiences in TB; (ii) for trainees, presenting TB cases is important for learning; (iii) for attendees of TB, discussion and collaboration surrounding the content of presentations has implications for learning; (iv) participants of TB are responsible for cultivating their learning environment and teaching one another; and (v) virtual TB alters the opportunity to participate and engage with the subject matter, impacting learning for participants. CONCLUSIONS: Exploring TB through the lens of an educational framework is a novel approach. By identifying the facilitators and inhibitors of learning in TB, opportunities to enhance the educational process in TB are now exposed. Our study illustrates that learning in TB occurs through the cognitive apprenticeship model, and provides insight on how to best cultivate this model to improve learning. These data demonstrate the social nature of learning, and how they align with the pediatric hematology/oncology community of practice.

Feasibility and early clinical impact of precision medicine for late-stage cancer patients in a regional public academic hospital.

AIM: Our goal was to describe a precision medicine program in a regional academic hospital, characterize features of included patients and present early data on clinical impact. MATERIALS AND METHODS: We prospectively included 163 eligible patients with late-stage cancer of any diagnosis from June 2020 to May 2022 in the Proseq Cancer trial. Molecular profiling of new or fresh frozen tumor biopsies was done by WES and RNAseq with parallel sequencing of non-tumoral DNA as individual reference. Cases were presented at a National Molecular Tumor Board (NMTB) for discussion of targeted treatment. Subsequently, patients were followed for at least 7 months. RESULTS: 80% (N = 131) of patients had a successful analysis done, disclosing at least one pathogenic or likely pathogenic variant in 96%. A strongly or potentially druggable variant was found in 19% and 73% of patients, respectively. A germline variant was identified in 2.5%. Median time from trial inclusion to NMTB decision was one month. One third (N = 44) of patients who underwent molecularly profiling were matched with a targeted treatment, however, only 16% were either treated (N = 16) or are waiting for treatment (N = 5), deteriorating performance status being the primary cause of failure. A history of cancer among 1st degree relatives, and a diagnosis of lung or prostate cancer correlated with greater chance of targeted treatment being available. The response rate of targeted treatments was 40%, the clinical benefit rate 53%, and the median time on treatment was 3.8 months. 23% of patients presented at NMTB were recommended clinical trial participation, not dependent on biomarkers. CONCLUSIONS: Precision medicine in end-stage cancer patients is feasible in a regional academic hospital but should continue within the frame of clinical protocols as few patients benefit. Close collaboration with comprehensive cancer centers ensures expert evaluations and equality in access to early clinical trials and modern treatment.