Druggable fusion gene landscape in solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13517-e13517
Author(s):  
Gareth Haydn Williams ◽  
Robert Paul Thatcher ◽  
Borja Nevado Polo ◽  
Tiffany Eira Haddow ◽  
Keeda-Marie Hardisty ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Solid Tumors ◽  
Fusion Gene ◽  
Real Life ◽  
Rare Event ◽  
Unknown Primary ◽  
Precision Oncology ◽  
Tumor Type ◽  
Fusion Genes ◽  
Fda Approval

e13517 Background: Kinases activated by gene fusions represent an important class of oncogenes in solid tumors highlighted by the unique site agnostic FDA approval of larotrectinib for NTRK gene rearrangements. However, the frequency and types of druggable fusions in solid tumors are not well characterized from the clinical perspective. Methods: Oncofocus is a clinically validated precision oncology platform that includes analysis of 399 druggable driver-partner oncogenic fusion genes linked to 140 unique targeted therapy protocols. A retrospective analysis of Oncofocus trending data in a real-life cohort of 1111 patients has been used to determine the actionable fusion gene landscape in solid tumors. Results: Eighty nine actionable fusion genes were identified in 1111 samples of solid tumors linked to 73 targeted therapy protocols. Seven of the samples harbored multiple fusion genes. Eighty two of the 1111 samples tested had at least one actionable fusion gene representing a frequency of 7.38%. The highest frequency of actionable fusions were observed in glioblastoma (23%), head and neck (12%), kidney (11%) and prostate (10%) cancers. Four of the seven samples with multiple actionable fusions were found in glioblastoma. Pancreatic, lung and endometrial cancers and cancer of unknown primary (CUPs) had an actionable fusion gene frequency ranging from 7-9%. TBL1XR1-PIK3CA, MET-MET, WHSC1L1-FGFR1 and EGFR VIII fusions were identified as the most common druggable fusions. All actionable fusion genes were found to interact with one or more of the following pathways RAS/RAF/MEK/ERK, PI3K/AKT/MTOR, PLCy/PKC and JAK/STAT. Although a targeted agent for TRK fusions now has FDA approval, this rearrangement appears to be a rare event. In contrast, inhibitors targeting the TBL1XR1-PIK3CA, MET-MET, WHSC1L1-FGFR1 fusions and linked downstream signalling pathways appear to offer much broader clinical utility. Conclusions: Druggable fusions were identified at an unexpectedly high frequency and should therefore be included as part of routine comprehensive precision oncology testing. Notably, many of the actionable fusions are not tumor type specific reinforcing the “site agnostic” approach to profiling and supporting the concept of “molecular basket” clinical trials. Precision oncology trending data also provides actionable mutational landscapes which can be used to refine precision oncology testing, patient selection for targeted therapy protocols and enhancement of clinical trial design.

The actionable genomic mutational landscape in solid tumours.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13642-e13642
Author(s):  
Marco Loddo ◽  
Keeda-Marie Hardisty ◽  
Robert Paul Thatcher ◽  
Tiffany Eira Haddow ◽  
Gareth Haydn Williams
Keyword(s):  
Dna Damage ◽  
Clinical Trials ◽  
Targeted Therapy ◽  
Genetic Variants ◽  
Real Life ◽  
Mapk Signaling ◽  
Precision Oncology ◽  
Tumor Type ◽  
First Line ◽  
Mutational Landscape

e13642 Background: The recent exponential increase in targeted agents and immunotherapies provide new therapeutic opportunities for patients with advanced cancers who have failed first line therapy. However, lack of comprehensive precision oncology testing as part of routine pathology assessment means potential therapeutic opportunities are difficult to identify or remain undiscovered for many patients. Methods: To address this unmet clinical need we established Oncofocus, a clinically validated, ISO15189/2012 and CLIA accredited, precision oncology test optimized for analysis of small diagnostic PWET clinical biopsy samples (sample acceptance 94%). Oncofocus detects actionable genetic variants in 505 genes linked to 764 anti-cancer targeted therapy protocols, either on-market FDA and EMA approved, carrying ESMO and NCCN guideline references or currently in clinical trials. Oncofocus trending data was analyzed for a real-life cohort of 1111 patients with the aim of determining the frequency of actionable mutations in this population. This cohort represent patients with advanced stage disease who underwent Oncofocus testing having failed first line treatment protocols. Results: Analysis of trending data revealed a complex mutational landscape in which 90% of solid tumors harbored actionable mutations. The majority of patients harbored one or more actionable mutations (median 2, range 0-13) affecting key cancer related regulatory networks including the PI3K/AKT/MTOR and RAS/RAF/MEK/MAPK signaling pathways, DNA-damage repair pathways and cell cycle checkpoints. Actionable genetic variants across 33 DNA Damage and Repair (DDR) genes were identified in 30% of tumors. Using a defined predictive cut point of > 10% for tumor proportion score, PD-L1 expression levels were significantly raised in 19% of cases. Abrogation of DDR function and elevated PD-L1 levels were identified in 5% of patients, a subpopulation potentially more responsive to immunotherapy. Notably, many of the actionable mutations identified did not show linkage with histological type or site of origin. Conclusions: Our data indicates that comprehensive precision oncology testing should be strongly considered as part of the diagnostic work up for all patients with advanced cancers, independent of tumor type, thereby ensuring capture of all targeted therapy opportunities and accelerating “site agnostic” molecular basket clinical trials. Comprehensive precision oncology testing was performed successfully on routine biopsy samples circumventing the requirement for fresh tissue or large sample specimens.

FoundationOne as a relevant tool for comprehensive genomic profiling and assessment of tumor mutation burden in the era of precision oncology in India.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23096-e23096
Author(s):  
Amit Verma ◽  
Nitesh Rohatgi ◽  
Pramod Kumar Julka ◽  
Meenu Walia ◽  
Ankur Bahl ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Mutation Frequency ◽  
Unknown Primary ◽  
Precision Oncology ◽  
Tumor Type ◽  
Genomic Profiling ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Types

e23096 Background: Comprehensive genomic profiling (CGP) is gaining acceptability globally, but clinical experience in developing countries like India is limited. CGP identifies genomic alterations (GA), with tumor mutation burden (TMB) and microsatellite status (MSI), revealing therapeutic options such as targeted inhibitors and immunotherapies. We sought to evaluate the mutation frequency and actionability across tumors. Methods: Metastatic and/or refractory patients (referred to Personalized Cancer Medicine Clinic) underwent CGP analysis, including calculation of TMB and MSI, using a targeted NGS panel (FoundationOne, 53 samples; FoundationOne Heme, 4 samples). This panel detects all relevant classes of GA: base substitutions, small indels, rearrangements and copy number changes. Mutation frequencies were compared with the larger Foundation database. TMB status was reported as low (≤5 mutations/Mb), intermediate (6-19 mut/Mb) or high (≥20 mut/Mb). Results: The most common tumor types were lung (23%), breast (14%) and sarcoma (12%); other tumor types, including unknown primary constituted the rest (51%). Most samples were from metastatic sites (60%). Oncogenic GA were found in 131 genes across all tumor subtypes and affected major pathways: apoptosis/cell cycle (31%), PI3K (14%), transcriptional regulation (13%), and receptor tyrosine kinases (10%). Among these GA, 38 were considered actionable and were distributed across 43 (75%) samples. Therapies with FDA approval for the tumor type analyzed were indicated for 18 samples; an additional 25 samples had GA associated with therapies FDA approved for another indication. More than 1 actionable GA was identified in 24/43 (56%). TMB status was low in 36 (63%), intermediate in 19 (33%) and high in 2 (3.5%). High TMB status correlated with high MSI status (p < 0.001). Trend observed in the mutation frequency was comparable with the larger Foundation database. Conclusions: This is the first study in India showing CGP identified actionable targets associated with FDA approved therapies in approx. 32% of cases. TMB status identified 2/57 samples with high mutation burden for whom immunotherapy might be relevant.

Therapy alteration of solid tumors based on FoundationOne comprehensive genome profiling assay.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14742-e14742
Author(s):  
Kirill Karlin ◽  
Abdullah Kahraman ◽  
Alessandra Curioni Fontecedro ◽  
Holger Moch ◽  
Martin Zoche ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Clinical Utility ◽  
Ductal Carcinoma ◽  
Treatment Plan ◽  
Subsequent Treatment ◽  
Unknown Primary ◽  
Tumor Type ◽  
Genome Profiling ◽  
New Therapy ◽  
Therapy Option

e14742 Background: Molecular profiling assays are becoming widely available and provide valuable information on tumor characteristics, which can identify targeted therapies or immunotherapies for cancer patients. However, the clinical utility of such tests remains unclear. Within our institution, we analyzed the clinical utility and subsequent treatment alterations of the FoundationOne Comprehensive Genome Profiling Test (FOne). Methods: We conducted a retrospective cohort review (2017 - 2018) of patients with solid tumors under standard diagnostic care who received FOne testing. We reviewed the therapies that were proposed by FOne and studied whether they led to a therapeutic alteration. Results: 71 patients were identified, of which the majority presented a progressive disease state (80%). Among the cancer types most frequently tested were adenocarcinoma of the colon (14%), prostate (8%), lung (4%), intrahepatic cholangiocarcinoma (8%) and breast invasive ductal carcinoma (4%). In 16 cases (22%), therapies suggested by FOne were approved in patient’s tumor type while in 30 cases (42%) therapies were approved in another tumor type. For an additional 13 cases (18%) only therapies tested in clinical trials were reported. 4 patients (6%) received a new therapy based on the FOne result: cancer of unknown primary (Everolimus due to a TSC1 mutation), cutaneous angiosarcoma (Pembrolizumab due to a high tumor mutational burden (TMB)), gastrointestinal neuroendocrine carcinoma (Ipilimumab and Nivolumab due to an intermediate TMB) and mucinous adenocarcinoma of the appendix (Talazoparib due to an ATM mutation). For 11 cases (15%), a new therapy option was identified by FOne, which due to the current treatment plan might be considered for later use. 3 cases (4%) were evaluated for potential clinical trial enrollment. Note that for an additional 6 patients (8%), the therapies proposed by FOne were already established on the basis of previous testing (e.g. smaller genomic panels, IHC, FISH). Conclusions: Overall, 18 (25%) patients received a new therapy option by FOne after standard of care diagnostics. Therapeutic alterations were observed particularly in patients with a rare or unknown tumor type.

Evaluation of a computational decision support system for molecularly targeted treatment planning by the clinical outcome data of the randomized trial SHIVA01.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3642-3642
Author(s):  
Anna Dirner ◽  
Robert Doczi ◽  
Peter Filotas ◽  
Barbara Vodicska ◽  
Edit Varkondi ◽  
...  
Keyword(s):  
Decision Support ◽  
Targeted Therapy ◽  
Decision Support System ◽  
Support System ◽  
Clinical Decision Making ◽  
Real Life ◽  
Molecular Profile ◽  
Evidence Based ◽  
Precision Oncology ◽  
Molecular Profiles

3642 Background: Precision oncology requires the identification of individual molecular pathomechanisms to find optimal personalized treatment strategies for every cancer patient. Incorporation of complex molecular information into routine clinical practice remains a significant challenge due to the lack of a reproducible, standardized process of clinical decision making. Methods: To provide a standardized process for molecular interpretation, we develop a precision oncology decision support system, the Realtime Oncology Molecular Treatment Calculator (MTC). MTC is a rule-based medical knowledge engine that dynamically aggregates and ranks relevant scientific and clinical evidence using currently 26,000 evidence-based associations and reproducible algorithm scoring of drivers, molecular targets to match molecular alterations to efficient therapies. To validate this novel method and system, we used data of the SHIVA01 trial of molecularly targeted therapy (Lancet Oncol 2015 16:1324-34). Molecular profiles of participants were uploaded to MTC and aggregated evidence level (AEL) values of associated targeted treatments were calculated, including those used in the SHIVA01 trial. Results: The MTC output provided a prioritized list of drugs associated with the driver alterations in the patient molecular profile, where ranking is based on AEL values. Of 113 patients who received targeted therapy with available clinical best response data, disease control was experienced in 63 cases (PR: 5, SD: 58), while disease progression occurred in 50 cases. The average AEL score for the therapies applied was significantly higher in the responsive group than in the non-responsive group (1512 and 614, respectively (p = 0.049)). In 94 cases, drugs other than those used for therapy were ranked higher by the MTC. The average AEL difference between the top-ranked and the used drugs was in an inverse correlation with clinical response, i.e. smaller differences associated with a better outcome. Conclusions: Results indicate that the aggregation of evidence-based tumor-driver-target-drug associations using standardized mathematical algorithms of this computational tool is a promising novel approach to improve clinical decisions in precision oncology. Further validation based on the results of other targeted clinical trials and real-life data using more detailed molecular profiles is warranted to explore the full clinical potential of this novel medical solution.

scholarly journals Targeted Therapy Recommendations for Therapy Refractory Solid Tumors—Data from the Real-World Precision Medicine Platform MONDTI

2020 ◽  
Vol 10 (4) ◽  
pp. 188
Author(s):  
Hossein Taghizadeh ◽  
Matthias Unseld ◽  
Martina Spalt ◽  
Robert M. Mader ◽  
Leonhard Müllauer ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Precision Medicine ◽  
Solid Tumors ◽  
Real World ◽  
Molecular Profile ◽  
Tumor Type ◽  
Therapy Recommendations ◽  
Dismal Prognosis ◽  
Advanced Therapy ◽  
Therapy Recommendation

Advanced therapy-refractory solid tumors bear a dismal prognosis and constitute a major challenge in offering effective treatment strategies. In this real-world retrospective analysis of our precision medicine platform MONDTI, we describe the molecular profile of 554 patients diagnosed with 17 different types of advanced solid tumors after failure of all standard treatment options. In 304 cases (54.9% of all patients), a molecular-driven targeted therapy approach could be recommended, with a recommendation rate above 50% in 12 tumor entities. The three highest rates for therapy recommendation per tumor classification were observed in urologic malignancies (90.0%), mesothelioma (78.6%), and male reproductive cancers (71.4%). Tumor type (p = 0.46), expression of p-mTOR (p = 0.011), expression of EGFR (p = 0.046), and expression of PD-L1 (p = 0.023) had a significant impact on the targeted therapy recommendation rate. Therapy recommendations were significantly more often issued for men (p = 0.015) due to gender-specific differences in the molecular profiles of patients with head and neck cancer and malignant mesothelioma. This analysis demonstrates that precision medicine was feasible and provided the basis for molecular-driven therapy recommendations in patients with advanced therapy refractory solid tumors.

Frequency of MET amplification determined by comprehensive next-generation sequencing (NGS) in multiple solid tumors and implications for use of MET inhibitors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11068-11068 ◽  
Author(s):  
Norma Alonzo Palma ◽  
Gary A. Palmer ◽  
Siraj M. Ali ◽  
Philip J. Stephens ◽  
Jeffrey S. Ross ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Solid Tumors ◽  
Base Pair ◽  
Unknown Primary ◽  
Tissue Samples ◽  
Met Amplification ◽  
High Level ◽  
Tumor Types ◽  
Homozygous Deletions ◽  
Next Generation Sequencing Ngs

11068 Background: MET expression has been shown to be prognostic and possibly predictive in several tumor types and both small molecule inhibitors of MET kinase as well as monoclonal antibodies are under study as therapies for this subset of patients. However, the methods to assess MET overexpression are not well standardized. In the clinic, NGS is an advanced diagnostic method for identifying known and unknown targeted-therapy options. We therefore sought to explore the ability of NGS to detect high level MET amplifications in a general oncology population. Methods: We review here the results from analysis of 2,221 FFPE tissue samples across a range of tumor types by an NGS assay in a CLIA-certified laboratory (Foundation Medicine). We specifically report base pair substitutions, small insertions/homozygous deletions (indels), high level (> 6 copies/nucleus) amplification (amp) and select rearrangements in 189 genes, including MET. Results: MET was altered in 28/2,223 (1.2%) of patient samples. MET alterations were limited to amplifications (median 15X, range 6X-40X); no base pair substitutions, indels, or rearrangements were found. MET amp was present in 3/48 (6.2%) primary bone sarcomas, 1/20 (5.0%) myogenic sarcomas, 2/58 (3.4%) gastric, 1/38 (2.6%) kidney, 2/78 (2.5%) hepatocellular, 1/41 (2.4%) uterine, 4/188 (2.1%) unknown primary, 2/99 (2.0%) ovarian, 8/386 (2.0%) lung, 3/157 (1.9%) colorectal, and 1/109 (0.9%) pancreatic carcinomas. Conclusions: Use of NGS to characterize MET alterations in a 2,000+ patient population provides evidence for the role of NGS in identifying the future use of MET-targeted therapy in a variety of common and uncommon solid tumors. Clinical follow-up of the subset of cases treated with a MET inhibitor is ongoing.

A preliminary single institution experience with droplet digital polymerase chain reaction (dd-PCR) liquid biopsy (LB) for therapeutic decision in advanced solid tumors: Personal precision oncology clinic and genetic diagnostics, Brazil.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14613-e14613
Author(s):  
Andre Marcio Murad ◽  
Jose Claudio Casali Rocha
Keyword(s):  
Polymerase Chain Reaction ◽  
Targeted Therapy ◽  
Solid Tumors ◽  
Genetic Diagnostics ◽  
Egfr Mutations ◽  
Precision Oncology ◽  
Advanced Solid Tumors ◽  
Chain Reaction ◽  
Polymerase Chain ◽  
Digital Polymerase Chain Reaction

e14613 Background: Droplet digital polymerase chain reaction (dd-PCR) is a promising method for analyzing minor amounts of cell-free circulating free nucleic acid (DNA and RNA) due to its high sensitivity, low cost, and fast reading, since it dispenses bioinformatics, making it an appropriate alternative to new generation sequencing (NGS) for the detection of biomarkers to guide molecularly targeted cancer therapy. The assay covers main actionable hotspot alterations across many actionable genes: EGFR(mutations), ALK (fusion, mutations), ROS1(fusion), BRAF(mutations), KRAS (mutations), NRAS(mutations), ERBB2(CNV), ESR1(mutations), KIT(CNV) and PDGFRA(CNV). Methods: We analyzed so far 38 patients with advanced NSCLC: 13(35%), breast: 9(24%), colorectal: 6(16%), pancreatic: 4(10%), ovary: 2(5%), salivary gland: 2(5%), melanoma 1(2.5%), and GIST: 1 (2.5%). ddPCR was performed using the QX200 system (BIO-RAD, Hercules). All samples were tested in duplicate. All assays were performed at Personal Precision Genetic Diagnostics. Belo Horizonte, MG. Brazil. Results: We detected meaningful genomic alterations in 7(18.5%) patients: 4(10.5%) KRAS G12V mutations (all in colorectal cancer), 1(2.6%) EGFR Del19 mutation, 1 EGFR L858R mutation(2.6%), both in NSCLC and 1(2.6%) ERBB2 amplification (in breast cancer). MAF (Mutant Allele Fraction) varied from 0.9% to 24%. In all cases the results were decisive for the indication or the change of a targeted therapy. Conclusions: Our preliminary results suggest that dd-PCR is a highly sensitive method and could be used for a routine laboratory detection of the important genomic variations to determine the targeted therapy in patients with varied advanced solid tumors.

scholarly journals Tumor Response Criteria in Oncoimaging: RECIST Criteria and beyond—Part 2

2019 ◽  
Vol 02 (02) ◽  
pp. 107-115
Author(s):  
Akshay D. Baheti ◽  
Ashita Rastogi ◽  
Aravintho Natarajan ◽  
Anurima Patra ◽  
Sree Harsha Tirumani
Keyword(s):  
Targeted Therapy ◽  
Solid Tumors ◽  
Tumor Response ◽  
Evaluation Criteria ◽  
World Health ◽  
Response Criteria ◽  
Precision Oncology ◽  
Disease Response ◽  
Choi Criteria ◽  
Tumor Response Criteria

AbstractThe rapid recent advances in oncology have made the dream of precision oncology a reality, with targeted therapy available for various tumors depending on the molecular genotype. This has led to the corresponding development of personalized radiology as well, with various tumor response criteria used to characterize disease response/progression depending on chemotherapy used. In these two review articles, we review the various tumor response criteria widely applied in both research and clinical settings. These include the classic size-based criteria such as RECIST (Response Evaluation Criteria In Solid Tumors) 1.1 and the WHO (World Health Organization) criteria, as also various other criteria such as Choi and modified Choi criteria for tumors treated by targeted therapy, EASL (European Association for the Study of the Liver) and modified RECIST (mRECIST) criteria for hepatocellular carcinomas, immune-related response criteria (irRC) and immune RECIST (iRECIST) for patients on immunotherapy. Other clinically important criteria such as PERCIST (PET Response Criteria In Solid Tumors) for positron emission tomography–computed tomography (PET-CT), and the MD Anderson criteria for evaluating bone metastases are also highlighted.

scholarly journals p65BTK Is a Novel Biomarker and Therapeutic Target in Solid Tumors

2021 ◽  
Vol 9 ◽  
Author(s):  
Emanuela Grassilli ◽  
Maria Grazia Cerrito ◽  
Sara Bonomo ◽  
Roberto Giovannoni ◽  
Donatella Conconi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Colon Cancer ◽  
Clinical Trials ◽  
Targeted Therapy ◽  
Cancer Patients ◽  
Solid Tumors ◽  
Low Grade ◽  
Tumor Type ◽  
Drug Resistant ◽  
Btk Inhibitors

Bruton’s tyrosine kinase (BTK) is a non-receptor intracellular kinase playing a key role in the proliferation and survival of normal and malignant B-lymphocytes. Its targeting by Ibrutinib, the first specific inhibitor, represented a turning point for the therapy of certain types of B-cell leukemias/lymphomas and several more BTK inhibitors are today in the clinic or advanced clinical trials. BTK expression was successively found to occur also outside of the hematopoietic compartment. In fact, we identified p65BTK, a novel 65 kDa isoform lacking an N-term stretch of 86 amino acids (compared to the 77 kDa protein expressed in B cells) as highly expressed in colon cancer patients. We demonstrated that p65BTK is a powerful oncogene acting downstream of the RAS/MAPK pathway and necessary for RAS-mediated transformation. Notably, the kinase domain is conserved and therefore inhibited by the available BTK-targeting drugs (Ibrutinib, Spebrutinib, etc.) which we used to demonstrate that p65BTK is an actionable target in drug-resistant colorectal carcinomas. We found p65BTK expressed also in &gt;50% non-small cell lung cancers (NSCLC) and demonstrated that it is an actionable target in KRAS-mutated/EGFR-wild type drug-resistant NSCLC models (for which no targeted therapy is available). We also reported a significant correlation between p65BTK expression and low-grade tumors and overall survival of patients with grade III gliomas and showed that its targeting induced a significant decrease in the viability of in glioma stem cells. Finally, in ovarian cancer patients, p65BTK expression levels correlate with early relapse and shorter progression-free survival, both indicators of resistance to therapy. Remarkably, Ibrutinib is more effective than standard of care (SOC) therapeutics in in vitro and ex vivo settings. On the whole, our preclinical data indicate that, depending on the tumor type, BTK inhibitors used alone can induce cytotoxicity (gliomas), be more effective than SOC chemotherapy (ovarian cancer) or can kill drug-resistant tumor cells when used in combination with SOC chemotherapy (colon cancer and NSCLC) or targeted therapy (NSCLC and ovarian cancer), thus suggesting that p65BTK may be an actionable target in different solid tumors. In addition, our data also give the proof-of-concept for starting clinical trials using BTK inhibitors, alone or in combination, to improve the therapeutic options for solid tumors treatment.

scholarly journals Implementation of a Molecular Tumor Registry to Support the Adoption of Precision Oncology Within an Academic Medical Center: The Duke University Experience

2021 ◽  
pp. 1493-1506
Author(s):  
Michelle F. Green ◽  
Jonathan L. Bell ◽  
Christopher B. Hubbard ◽  
Shannon J. McCall ◽  
Matthew S. McKinney ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Medical Center ◽  
Academic Medical Center ◽  
Tumor Board ◽  
Precision Oncology ◽  
Tumor Type ◽  
Genomic Profiling ◽  
Multiple Sources ◽  
Duke University ◽  
The Right

PURPOSE Comprehensive genomic profiling to inform targeted therapy selection is a central part of oncology care. However, the volume and complexity of alterations uncovered through genomic profiling make it difficult for oncologists to choose the most appropriate therapy for their patients. Here, we present a solution to this problem, The Molecular Registry of Tumors (MRT) and our Molecular Tumor Board (MTB). PATIENTS AND METHODS MRT is an internally developed system that aggregates and normalizes genomic profiling results from multiple sources. MRT serves as the foundation for our MTB, a team that reviews genomic results for all Duke University Health System cancer patients, provides notifications for targeted therapies, matches patients to biomarker-driven trials, and monitors the molecular landscape of tumors at our institution. RESULTS Among 215 patients reviewed by our MTB over a 6-month period, we identified 176 alterations associated with therapeutic sensitivity, 15 resistance alterations, and 51 alterations with potential germline implications. Of reviewed patients, 17% were subsequently treated with a targeted therapy. For 12 molecular therapies approved during the course of this work, we identified between two and 71 patients who could qualify for treatment based on retrospective MRT data. An analysis of 14 biomarker-driven clinical trials found that MRT successfully identified 42% of patients who ultimately enrolled. Finally, an analysis of 4,130 comprehensive genomic profiles from 3,771 patients revealed that the frequency of clinically significant therapeutic alterations varied from approximately 20% to 70% depending on the tumor type and sequencing test used. CONCLUSION With robust informatics tools, such as MRT, and the right MTB structure, a precision cancer medicine program can be developed, which provides great benefit to providers and patients with cancer.

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